Background: Implant-based reconstruction (IBR) is the most common method of breast reconstruction in the United States. Despite ongoing advancements, periprosthetic infection is a serious problem that often results in device explantation. The objective of this study was to evaluate the outcomes of third-attempt reconstruction in patients in whom secondary implant-based reconstruction failed because of infection. Methods: The authors performed a retrospective review of patients who underwent mastectomy followed by IBR from 2000 to 2019. The outcomes of patients in whom secondary IBR failed because of infection and who ultimately underwent third-attempt breast reconstruction were analyzed. Results: Of 6093 patients who underwent primary IBR, 13 patients had third-attempt breast reconstruction following infection-related explantation [median age, 52 years (interquartile range, 51 to 56 years); median body mass index, 23 kg/m2 (interquartile range, 22 to 31 kg/m2); median follow-up, 46 months (interquartile range, 16 to 62 months)]. Nine patients (70%) underwent IBR, two (15%) underwent IBR combined with pedicled latissimus dorsi flap, and two (15%) underwent abdominally based free tissue transfer. Third-attempt breast reconstruction was immediate in 46% of patients and delayed in 54%. The success rate was 78% in the IBR group, with a 23% complication rate. The success rate for autologous breast reconstruction was 100%, with one patient developing venous congestion necessitating return to the operating room. Conclusions: Third-attempt breast reconstruction following infection-associated failed secondary IBR is a safe and feasible option. Although the risk of failure is higher than that for primary implant-based reconstruction, a third attempt after secondary IBR infection had a surprisingly high 78% success rate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.