BACKGROUND: Mastectomy flap necrosis (MFN) is a common complication of immediate breast reconstruction that greatly affects patient satisfaction and cosmetic outcomes. Topical nitroglycerin ointment, with its low cost and negligible side effects, has been shown to significantly decrease the incidence of MFN in immediate implant-based breast reconstruction, but its utility has not been studied in immediate autologous reconstruction. METHODS: With institutional review board approval, a prospective cohort study was performed of all consecutive patients undergoing immediate free-flap breast reconstruction by a single reconstructive surgeon at a single institution between February of 2017 and September of 2021. Patients were divided into two cohorts: those who received 30 mg of topical nitroglycerin ointment to each breast at the conclusion of the operation (September of 2019 to September of 2021) and those who did not (February of 2017 to August of 2019). All patients underwent intraoperative SPY angiography, and mastectomy skin flaps were débrided intraoperatively based on imaging. Independent demographic variables were analyzed, and dependent outcome variables included mastectomy skin flap necrosis, headache, and hypotension requiring removal of ointment. RESULTS: A total of 35 patients (49 breasts) were included in the nitroglycerin cohort and 34 patients (49 breasts) were included in the control group. There was no significant difference in patient demographics, medical comorbidities, or mastectomy weight between cohorts. The rate of MFN decreased from 51% in the control group to 26.5% in the group that received nitroglycerin ointment ( P = 0.013). There were no documented adverse events associated with nitroglycerin use. CONCLUSION: Topical nitroglycerin ointment significantly decreases the rate of MFN in patients undergoing immediate autologous breast reconstruction without significant adverse effects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.