The 5-factor modified Frailty Index (mFI-5) is a risk-stratification tool utilized to predict complications and mortality following major lower extremity (LE) amputation. However, its prognostic value for long-term mortality is unknown. The study aim was to assess whether a high mFI-5 score relates to long-term mortality following major LE amputation for chronic wounds. Patients ≥60 years who underwent major LE amputation from 2017 to 2021 were retrospectively reviewed. Data regarding demographics, comorbidities, perioperative factors, amputation type, and postoperative complications was collected and mFI-5 was calculated. Survival analysis was performed with Kaplan-Meier curves and differences were assessed with Log-Rank test. A total of 172 patients were identified. Mean age was 70.7 ± 8.0 years. Median time to ambulation was 3.7 months (IQR 4.0). By final follow-up of 17.5 ± 15.9 months, ambulatory rate was 51.7% (n=89), overall mortality 36.0% (n=62), one-year mortality 14.0% (n=24), and three-year mortality 27.9% (n=48). Patients with an mFI-5 of ≥4 (26.7%, n=46) compared with patients with mFI-5 <4 (73.3%, n=126) had a higher rate of prolonged postoperative LOS (34.8% vs. 19.8%, p=0.042), overall mortality (52.2% vs. 30.2%, p=0.008), one-year mortality (23.9% vs. 10.3%, p=0.023), and three-year mortality (45.7% vs. 21.4%, p=0.002). Multivariate analysis demonstrated mFI-5 was an independent predictor of three-year mortality (OR 2.35, p=0.043). At a threshold ≥4, the mFI-5 demonstrated utility in predicting long-term mortality. The value of this prognostic indicator is in its preoperative application of assessing risk of mortality, which should be utilized in conjunction with other measures.