Objective To systematically review management of flap loss in head and neck construction with free tissue transfer as compared with locoregional flap or conservative management. Data Sources Medline, Embase, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov were searched up to October 2019. Review Methods Candidate articles were independently reviewed by 2 authors. Articles were considered eligible if they included adequate reporting of flap management after flap loss and outcomes for survival of reconstruction, length of hospitalization, and perioperative complications. Results A total of 429 patients had acute flap failure in the perioperative period. The overall success with a secondary free flap was 93% (95% CI, 0.89-0.97; n = 26 studies, I2 = 12.8%). There was no difference in hospitalization length after secondary reconstruction between free tissue transfer and locoregional flaps or conservative management (relative risk of hospitalization ≥2 weeks, 96%; 95% CI, 0.80-1.14; n = 3 studies, I2 = 0). The pooled relative risk of perioperative complications following free tissue transfer was 0.60 when compared with locoregional flap or conservative management (95% CI, 0.40-0.92; n = 5 studies, I2 = 0). Conclusion Salvage reconstruction with free tissue transfer has a high success rate. Second free flaps following flap failure had a similar length of hospitalization and lower overall complication rate than locoregional reconstruction or conservative management. A second free tissue transfer, when feasible, is likely a more reliable and effective procedure for salvage reconstruction.