BACKGROUND: Attempts to identify risk factors for adverse outcome following skin-sparing mastectomy and immediate prosthetic reconstruction have yielded inconsistent results, and no clear patient selection criteria have emerged. The authors identified patient- and procedure-related characteristics that predict unfavorable postoperative outcomes. Knowledge of these risk factors will facilitate preoperative patient screening to reduce the rate of implant loss and other postoperative complications. METHODS: The authors retrospectively evaluated the postoperative outcomes of implant loss and major and minor complications in 102 patients (155 breasts) undergoing the combined operation from January of 2005 to December of 2010. Univariate logistic regression analysis was performed to determine the influence of six patient-related and three procedure-related characteristics on implant loss and postoperative complications. RESULTS: The use of acellular dermis was associated with a greater than three-fold increased risk of postoperative complications. Radiotherapy exposure was found to have a significant association with implant loss. None of the patient-related characteristics studied behaved as risk factors for postoperative complications, and none of the procedure-related characteristics acted as risk factors for implant loss. CONCLUSIONS: A cautious and conservative approach to using acelluar dermal matrix in this setting is warranted until its effect on postoperative outcomes is more clearly defined. The authors' data support findings from other studies of the deleterious effect of breast radiotherapy on postoperative outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.