Background: Two-stage prosthetic breast reconstruction with initial insertion of a tissue expander followed by an implant after a period of inflation is a well-established breast reconstruction option. Most of the current literature concentrates on the immediate setting, and there are only a few reports into delayed cases, especially after postmastectomy radiotherapy (RT). We performed a retrospective review of our experience over a 12.5-year period. Methods: Between June 1998 and December 2010, a total of 671 patients received prosthetic-only breast reconstruction. Of these, 170 (25.3%) underwent delayed 2-stage prosthetic breast reconstruction after mastectomy for cancer. Patients were divided into group A, no postmastectomy RT (n = 150), and group B, postmastectomy RT (n = 20). The primary factor examined was the failure of the reconstruction from loss of prosthesis with or without smoking. Other complications, as well as rates of revisional surgery were also recorded. Results: Expander or implant loss occurred in 3 of 150 patients in group A (2.0%) and 3 of 20 patients in group B (15%; P = 0.02). For nonsmokers, implant loss was 1.6% and 5.6%, respectively (P = NS). Smoking was associated with 1 of the 3 losses in group A and 2 of the 3 in group B (smokers, n = 2; P < 0.01). There was no significant difference in other complications such as seromas or minor wound infections. Conclusions: Delayed 2-stage prosthetic breast reconstruction has a low failure rate. It can also be successfully completed in selected patients after postmastectomy RT, but care must be taken with patients who smoke.