This study examined the correlation between preoperative transcutaneous oxygen perfusion (TcPO2) measurement and the success of wound healing after major lower extremity amputation. There is no validated consensus on how to accurately determine appropriate amputation levels. A TcPO2 greater than 30 to 40 mm Hg is widely cited as a positive predictor of postoperative wound healing, but its validity has not been well defined. A retrospective chart review was performed for patients who underwent above-knee amputation (AKA), through-knee amputation, or below-knee amputation (BKA) at a single institution from 2012 to 2018 with preoperative TcPO2 values and a minimum 30-day postoperative clinical follow-up. This review yielded 141 total amputations: 93 BKAs, 6 through-knee amputations, and 42 AKAs. Fifty-five amputations were unsuccessful, defined by postoperative wound dehiscence or infection. Of these, 37 were BKAs, 4 were through-knee amputations, and 14 were AKAs. There was a significant difference in preoperative TcPO2 between the successful and unsuccessful amputations, at 46.2 and 38.3 mm Hg, respectively (P=.02). A TcPO2 of 30 to 40 mm Hg showed a 68.8% success rate, and a TcPO2 of less than 20 mm Hg showed an 18.2% success rate. A receiver operating characteristic curve for TcPO2 predicting amputation success had an area under the curve of 0.53 for AKAs and 0.61 for BKAs; the diagnostic ability is far from prognostic. There is no linear association between TcPO2 and success rate. A TcPO2 of less than 20 mm Hg has a high positive predictive value for failure, but higher levels are not 100% predictive of wound healing success after amputation, as previously reported. [Orthopedics. 2022;45(3):174-180.].