The 45-year-old Italian had been at the helm of Ducati's MotoGP project since its race-winning 2003 debut, and was in charge of the engineering of the Desmosedici machine through the successful Casey Stoner era and the subsequent Valentino Rossi disaster.
His position as general manager became increasingly perilous however as Rossi's dissatisfaction with Ducati's efforts grew last year.
New Ducati owners Audi elected to replace him with Bernhard Gobmeier, former director of BMW's World Superbike programme, in November last year.
Preziosi was due to take up a new role as head of R&D at Ducati Motor Holding, but has now resigned due to poor health.
Ducati said it reluctantly accepted his resignation and that a successor will be announced in due course.
"Engineer Filippo Preziosi has communicated his intention to resign from his position at Ducati Motor Holding," a statement read.
"Declaring reasons of poor health related to his particular physical condition, Preziosi's resignation was accepted by Ducati, saddened and disappointed to lose such an accomplished and strategic member of staff.
"The company respectfully acknowledges the 45-year old Italian's decision and thanks him for his significant contribution during his 19 years with Ducati, 12 of which were within Ducati Corse.
"Previously occupying the role of General Manager of Ducati Corse, Preziosi, was appointed Director of Research and Development of Ducati Motor Holding at the end of 2012 and was to start his new role after a period of rest.
"An announcement of the successor to this strategic role, now left vacant by the resignation, will be communicated in due course."