In this retrospective study of threatened mastectomy skin flaps after immediate tissue expander reconstruction, the addition of outpatient topical tacrolimus at discharge to an existing inpatient nitroglycerin-based protocol was associated with lower rates of postoperative necrosis. Building on our prior preclinical rodent data showing improved flap survival with topical tacrolimus, we compared consecutive cases of threatened mastectomy skin flaps. There were 33 breasts treated under the newer nitroglycerin plus tacrolimus protocol and 48 breasts treated under the prior protocol, which used nitroglycerin followed by bacitracin or silver sulfadiazine. Baseline demographic, comorbidity, and mastectomy characteristics were similar between groups. Tacrolimus use was associated with a significantly lower rate of any necrosis, defined as partial- or full-thickness necrosis (21.2% vs 43.8%, p=0.032), while full-thickness necrosis was also less frequent (9.1% vs 22.9%) but did not reach statistical significance. These findings suggest that topical tacrolimus may be a promising adjunct in the management of threatened mastectomy flaps, though larger prospective studies are needed.