Background: The authors performed a systematic review of the literature on the outcome of therapy for patients with breast cancer who underwent adjuvant radiotherapy after an immediate two-stage prosthetic breast reconstruction, either following tissue expansion (stage 1) or after removal of the tissue expander and insertion of a final breast implant (stage 2). Their outcomes were compared to those of patients who had reconstruction without postmastectomy irradiation. Methods: Electronic database searches were supplemented by a full-text review of possible relevant articles on two-stage prosthetic immediate breast reconstruction and radiotherapy. Delayed or one-stage prosthetic or nonprosthetic breast reconstruction studies were excluded. The primary outcome measured was the reconstruction failure rate with prosthesis loss. Secondary endpoints were capsular contracture and aesthetic outcome. Results: No randomized controlled trials were identified, and only one prospective, nonrandomized, multicenter trial was found. Reports with more than 15 patients were included; 12 studies had a total of 1853 patients (715 irradiated and 1138 nonirradiated). Adjuvant radiotherapy resulted in a significantly higher reconstruction failure rate in immediate two-stage prosthetic breast reconstruction compared with controls (18.6 percent versus 3.1 percent, p < 0.00001). Radiotherapy particularly increased the failure rate when given after stage 1 (expander) (29.7 percent versus 5 percent, p < 0.00001) but also stage 2 (permanent implant) (7.7 percent versus 1.5 percent, p = 0.0003). There was also an increase in severe capsular contractures and an inferior cosmetic result in the irradiated patients. Conclusion: Nonrandomized studies suggest that adjuvant radiotherapy results in a higher risk of reconstruction failure.