Colombia, equal on 26 points with Argentina at the top of the South American group, can also book their passage to next year's finals in Brazil with a draw against Uruguay at the Centenario in Montevideo (2200 GMT).
Along with third-placed Chile, who have a bye, the top three are guaranteed of at least reaching the fifth-place playoff against an Asian qualifier.
Romero, who made his debut in a 1-0 defeat in the equivalent fixture in Asuncion under then coach Diego Maradona on the way to the 2010 finals in South Africa, is eyeing Sergio Goycochea's 26-match Argentina record.
Penalty specialist "Goyco" had his unbeaten run between Argentina's defeat in the 1990 World Cup final in Rome and a 2-1 loss in a qualifier in Colombia in August 1993.
Romero returns to the side along with captain Lionel Messi and striker Sergio Aguero after the trio missed the 2-1 friendly win over Italy in Rome last month.
A victory will secure Argentina's passage to the finals but they may go into their match at the Defensores del Chaco (0140 GMT Wednesday) having already done so without yet playing.
Argentina's match is the last of four South American qualifiers on Tuesday and results in earlier clashes could ensure they finish in the top four places in the group and qualify.
The fifth-placed team, at present Uruguay, will go into a two-legged playoff against the winners of an Asian decider between Uzbekistan and Jordan.
Coach Alejandro Sabella will have another chance to test his team-building, fielding a side lacking four first choice players through suspension and left back Marcos Rojo due to injury.
Striker Gonzalo Higuain is serving the second of a two-match ban and midfielder Javier Mascherano the first while centre backs Ezequiel Garay and Federico Fernandez have accumulated two bookings each.
"Against Bolivia (in March), there were also many changes and we did well. The way the team functions is always the same," Romero told reporters.
However, Sabella welcomes back Fernando Gago, whose midfield playmaking affords Messi the freedom to play just behind the strikers across the face of attack where he makes the most damage.
Rival coach Victor Genes is rejuvenating a Paraguay side who have lost any realistic chance of going to the finals for the fifth time in a row.
He has promoted several promising players from the under-20s he managed before landing the top job in July and the team have responded by crushing Bolivia 4-0 in his first qualifier in charge on Friday.
Uruguay have bounced back from their 2012 slump and are on course to at least reach the finals via the playoff, but against Colombia they will be without suspended central defenders Diego Lugano and Diego Godin and injured left back Martin Caceres and forward Diego Forlan.
Colombia's 1-0 win over Ecuador in a downpour in Barranquilla on Friday ensured they would at least reach the playoffs and remain on course to reach the finals for the first time since France 98.
Fourth-placed Ecuador, who play their home games at 2,800 metres in Quito, must impose their comfort with the thin Andean air at high altitude against eliminated Bolivia, who entertain all visitors at 3,600 in La Paz (2000).
Venezuela, who have never been to the finals, and Peru, last there at Spain 82, clash in Puerto La Cruz (2355) with both needing to win to stay in the hunt.