Scores of riders hit the deck towards the foot of the final Cat.4 climb as heavy showers made the roads treacherously slippery just as the peloton was in full swing.
Italian Giampaolo Caruso (Katusha) was taken straight to hospital after lying motionless on the tarmac for a long while as fellow riders picked themselves off the ground.
Caruso's Katusha team-mate Joaquim Rodriguez - one of the pre-race favourites - was involved in the same incident and crossed the finish line more than seven minutes down on Matthews. The Spaniard was reportedly taken to hospital for X-rays on his left wrist.
After picking up maximum bonus seconds over the line, Orica-GreenEdge's Matthews now leads Evans by 21 seconds on GC, with Colombian Rigoberto Uran of Omega Pharma-Quick Step - who crossed the line in a chasing group some 49 seconds down - in third, at 1:18.
Another Colombian - the much fancied climber Nairo Quintana of Movistar - avoided coming off his bike but is now 2:08 down in the overall standings in tenth place.
The horrific incident occurred 10km from the end of the 257km stage from Sassano - the longest of this year's race - after a cluster of riders skidded off the side of the road at top speed, most notably Astana's Janez Brajkovic, who hurtled into a road barrier.
A second, larger pile-up then ensued moments later as the riders entered a roundabout. Poland's Przemyslaw Niemiec (Lampre-Merida), former maglia rosa Svein Tuft (Orica-GreenEdge), Dutchman Rick Flens (Belkin) and local boy Stefano Pirazzi (Bardiani) were just a handful of numerous riders badly affected by the crash.
Riding on the front of the pack with his BMC team-mates, Evans avoided the incident despite its close proximity, making no decision to sit up and wait for a regrouping.
A group of eight riders - BMC's Evans, Daniel Oss, Steve Morabito and Ivan Santaromita, GreenEdge's Matthews and Luke Durbridge, Lotto Belisol's Tim Wellens and Neri Sotteri's Matteo Rabbotini - started the climb with 30-odd seconds on the chasing group.
Oss and Durbridge were first to drop back, while Morabito and Santaromita followed inside the final two kilometres. Behind a frantic but fractious effort was being made by disparate riders to close the gap, with Croatia's Robert Kiserlovski (Trek) managing to break clear.
Evans surged clear underneath the 1km-to-go banner but Matthews held his wheel, the youngster sweeping past the man 14 years his senior to take a quite superb victory - his first on the Giro.
Evans was pipped to second by the impressive Belgian Wellens, with Rabottini settling for fourth. Dutch youngster Wilco Kelderman (Bekin) led the chasing group over the line 49 seconds in arrears before the main field arrived, bloodied and bruised, in dribs and drabs after another weather-stricken stage in Italy.
FOUR-MAN GROUP: Colombian Rodolfo Torres (Colombia) and Italians Andrea Fedi (Neri-Sottoli), Marco Bandiera (Androni Giocattoli) and Edoardo Zardini (Bardiani-CSF) broke clear early on after countering a move by Dutch national champion Johnny Hoogerland (Androni). The four leaders built up a maximum lead of 14 minutes over the peloton as the race edged past Naples, but they were caught inside the final 15km ahead of the dramatic finale.
BIG WINNER OF THE DAY: Cadel Evans, 37, shook his head as he crossed the line in third place - perhaps in reflection to the utter carnage that had come from those previous crashes rather than any true disappointment at missing out on the win.
For Evans was clearly the big beneficiary of the day - surging clear in the battle for GC but without having the stress of taking the maglia rosa thanks to the steely presence of his compatriot, Matthews. As for Matthews - well, he said that he was climbing better than he was sprinting, and that was proved the case here. What a masterful final climb from the pocket-rocket from GreenEdge, who is making a stunning debut in Italy.
BIG LOSERS OF THE DAY: Crossing the line 7:43 down on his rival Evans, Joaquim Rodriguez's chances of winning the Giro d'Italia are over - although he will probably be more concerned about the well-being of his team-mate Giampaolo Caruso after his sickening fall.
Ireland's bad luck in the race continues after Nicolas Roche - the cousin of Dan Martin, who crashed out on the opening day - lost 15 minutes after being caught up in the crash. Tinkoff-Saxo will now put all their eggs in Rafal Majka's basket, the Pole crossing the line in the chasing group 49 seconds adrift.
KEY MOMENT: Those back-to-back crashes ahead of the final climb 10km from the finish changed the dynamic of the race - perhaps irrevocably.
TALKING POINT: Were Cadel Evans and his BMC team right to continue their ferocious pace following the incident? Already Twitter and online forums are awash with both support and criticism - with some people claiming it was the kind of unfortunate race incident that has derailed Evans on so many occasions in the past, and others angry that a greater sense of fair-play was not shown by BMC and GreenEdge.
Even though Evans had a wonderful day in the saddle, you do get the impression that there will be a bitter taste in the mouth following the controversial conclusion of the stage.
COMING UP: Friday's 211km stage seven from Frosinone to Foligno is a lumpy affair featuring two lower-categorised climbs. It finishes with a downhill followed by a 20km flat run-in and so we can expect a mass bunch sprint - the first since Marcel Kittel packed his bags and the race arrived on Italian soil.
Stage six result
1. Michael Matthews (Australia / Orica) 6:37:01"
2. Tim Wellens (Belgium / Lotto) ST
3. Cadel Evans (Australia / BMC Racing)
4. Matteo Rabottini (Italy / Neri Sottoli)
5. Ivan Santaromita (Italy / Orica) +13"
6. Steve Morabito (Switzerland / BMC Racing) +23"
7. Wilco Kelderman (Netherlands / Belkin) +49"
8. Mauro Finetto (Italy / Neri Sottoli)
9. Diego Ulissi (Italy / Lampre)
10. Fabio Duarte (Colombia / Colombia)
1. Michael Matthews (Australia / Orica) 24:18:14"
2. Cadel Evans (Australia / BMC Racing) +21"
3. Rigoberto Uran (Colombia / Omega Pharma - Quick-Step) +1:18"
4. Steve Morabito (Switzerland / BMC Racing) +1:25"
5. Matteo Rabottini (Italy / Neri Sottoli)
6. Ivan Santaromita (Italy / Orica) +1:47"
7. Fabio Aru (Italy / Astana) +1:51"
8. Tim Wellens (Belgium / Lotto) +1:52"
9. Ivan Basso (Italy / Cannondale) +2:06"
10. Nairo Quintana (Colombia / Movistar) +2:08"
- Sports & Recreation
- Cadel Evans
- Steve Morabito
- Ivan Santaromita
- Tim Wellens