The purpose of this study was to evaluate health-related quality of life after major lower-extremity amputation in a cohort of patients with diabetes mellitus. We evaluated 81 patients with diabetes and transtibial amputation (TTA) who had a minimum of 1 year of follow-up. Of these 81 patients, 50.6% completed the Short Form Survey (SF-36) and the Foot and Ankle Ability Measure (FAAM) preoperatively and postoperatively. Outcome measures before and after TTA were compared using Welch’s ANOVA for continuous variables and Fisher’s exact test for categorical variables. There was significant improvement in all 8 subscales of the SF-36, physical component summary (PCS) score, mental component summary (MCS) score, and the FAAM. The median SF-36 PCS score improved from 26.2 to 36.6 preoperatively versus postoperatively (P < .0005). The postoperative PCS score improved in 75.6% of patients and worsened in 24.4%. The median SF-36 MCS score improved from 43.7 to 56.1 preoperatively versus postoperatively (P < .0005). Both the FAAM activities of daily living (ADL; P < .005) and FAAM sports scores (P < .05) improved significantly. The postoperative FAAM general/ADL score improved in 75.6% of patients and worsened in 24.4%. Patients who were nonambulatory postoperatively had significantly lower SF-36 general health subscale scores and lower FAAM scores than patients who were ambulatory postoperatively. In select patients with nonfunctional lower extremities resulting from instability and/or chronic infection, TTA can result in significant improvement in quality of life and lower-extremity function. We acknowledge that 25% of patients had a reduction in self-reported quality of life; however, 75% of patients improved their quality of life.