The aim of this study was to evaluate the impact of end-stage renal disease (ESRD) on health-related quality of life (QOL) in patients with diabetic foot disease. We compared a group of 30 diabetic patients with ESRD requiring dialysis to a group of 60 diabetic patients without ESRD. Both groups consisted of patients with active diabetic foot disease (ulcer, Charcot, infection) and were matched with regard to age and gender. Self-reported QOL was assessed using the Short Form-36 (SF-36) physical and mental component summary (PCS and MCS) scores and the region-specific Foot and Ankle Ability Measure (FAAM). Diabetic foot patients with ESRD requiring dialysis were found to have significantly higher creatinine levels, lower hemoglobin levels, lower albumin levels, higher rates of peripheral arterial disease, and lower rates of Charcot neuroarthropathy than patients without ESRD. The median PCS was significantly lower in the ESRD group; however, no significant difference was found when comparing the median MCS and FAAM. Patients who ultimately died had a tendency to report lower PCS scores at baseline compared with those patients who did not die (P = .07). Patients who ultimately required major amputation also reported lower PCS scores at baseline. ESRD negatively affects physical QOL to a greater degree than mental QOL in patients with diabetic foot disease. The SF-36 may not be sensitive enough to capture impaired mental QOL because both groups had relatively high MCS scores. Low physical QOL may be associated with mortality and the eventual need for major amputation.