Simonetta became sick with consumption (tuberculosis) and the prognosis was grim. A distraught Giuliano, unwilling to lose his beloved, decided that keeping Simonetta alive as a vampire was better than letting her die. He summoned Dominic Salcedo, the city's foremost vampire hunter, and gave him a top secret mission: capture a vampire and bring it back to the palace. Salcedo, unwilling to disobey one of the city's most powerful men, complied and, the following night, an unfortunate vampire was brought to the room in the palace where Simonetta lay dying. The vampire bit her and was then destroyed. Within two days, Simonetta herself had turned.

Though Giuliano must have been shocked when he first saw Simonetta, with her black eyes and ghastly color, he was pleased to discover that she recognized him and remembered their life together. Like many a hopeless romantic, Giuliano mistakenly decided that the love Simonetta had for him would trump any bloodlust she felt. And so when she beckoned him with kind words, he eagerly went to her, and was bitten. That night, Lorenzo de Medici discovered his brother in the throes of transformation, with telltale wounds on his neck. For a second time, Dominic Salcedo was summoned. Salcedo and his team searched the enormous palace for Simonetta, eventually finding her in the bell tower. Cornered, Simonetta jumped to her death on the plaza below, the same plaza where, only weeks earlier, hundreds had jousted in her honor. Per his request, Giuliano was buried at her feet.