Background: Little is known about the outcomes following major limb-sparing treatment (treatments avoiding below-knee amputation) in diabetic or non-diabetic patients with foot and ankle infection. This study was to compare patient-reported outcomes (PROs) and health-related quality of life (HrQoL) of diabetic and non-diabetic patients with foot and ankle infections in both pre-and post-treatment (major limb-sparing treatment) periods. Methods: This study included a total number of twenty-six patients who were divided as 15 patients with diabeticrelated foot and ankle infection and 11 patients who had foot and ankle infections without diabetes mellitus (DM). Baseline characteristics including site of infection, PROs via visual analogue scale foot and ankle (VASFA) score, and HrQoL via Short-Form (SF)-36 score were recorded in each patient. VASFA and SF-36 scores were compared between the two groups in both pre-and post-treatment periods. Results: Mean follow-up time was 11.1 months. There were significant improvements of the VASFA score and SF-36 score regarding the pre-and post-treatment periods (p<0.001). The correlations between the VASFA score and SF-36 score were significant in both the pre-(r = 0.469; p = 0.024) and post-treatment periods (r = 0.772; p<0.001). The variables as height, weight, body mass index (BMI) included pre-and post-treatment VASFA scores and SF-36 scores were no significant differences (p>0.05). Conclusions: Regarding foot and ankle infection, the patients with and without DM could undergo the comparable results via patients’ PROs and HrQoL assessment following the major limb-sparing treatments.