Necrosis of a cutaneous flap including the nipple-areolar complex is a common complication in immediate implant-based breast reconstruction following nipple/skin-sparing mastectomy (NSM/SSM). This study aimed to evaluate the efficacy of prostaglandin E1 (PGE1) in reducing such complications. A retrospective analysis of prospectively collected data was conducted at two centers, and the cohort consisted of patients undergoing NSM/SSM followed by immediate reconstruction with a prosthesis. Patients who were randomly allocated to the treatment group were administered daily intravenous PGE1 (10 mcg/2 mL) beginning intraoperatively through postoperative day 6. Skin flap complications including nipple/skin necrosis, delayed wound healing, and postoperative wound revision were recorded. Complication rates were compared between the PGE1 and control groups. A total of 276 breasts in 259 patients were included for analysis (139 breasts to the treatment group and 137 breasts to the control group). There was no difference in patient demographics between the control and treatment group. Reconstructed breasts receiving PGE1 had significantly lower rates for overall skin complications (21.6% vs. 34.3%, p=0.022) and wound revision (2.9% vs. 9.5%, p=0.025). Among NSM cases, the PGE1 group showed a significantly lower rate of nipple necrosis (15.5% vs. 29.4%, p=0.027). In the multivariate analysis, the use of PGE1 significantly reduced the risk of overall skin flap complications (odds=0.491, p=0.018), wound revision (odds=0.213, p=0.018) in NSM/SSM cases, and nipple necrosis (odds=0.357 p=0.008) in NSM cases. PGE1 can be effective in reducing risk of mastectomy flap complications in immediate implant-based breast reconstructions.