This study was undertaken to assess the benefits of negative-pressure wound therapy (NPWT) versus traditional wound therapies in reducing the incidence of lower-extremity amputations in patients with diabetic foot ulcers. Administrative claims data for patients with diabetic foot ulcers from commercial payers (n=3,524) and Medicare (n=12,795) were retrospectively analyzed. Patients were divided into NPWT and control/traditional therapy groups on the basis of administrative codes. Risk-adjustment procedures were then performed to match patient risk categories (through total treatment costs) and wound severities (through debridement depth). The incidence of amputations in the NPWT groups was lower than that in the control groups. For the cost-based risk-adjustment analysis, amputation incidences with NPWT versus traditional therapy were 35% lower in the Medicare sample (10.8% versus 16.6%; P=.0077) and 34% lower in the commercial payer sample (14.1% versus 21.4%; P=.0951). Whereas overall amputation rates increased progressively with increasing wound debridement depth in both control groups, the same increasing trend did not occur in the NPWT groups. Patients with diabetic foot ulcers in the Medicare sample treated with NPWT had a lower incidence of amputations than those undergoing traditional wound therapy; this finding was evident in wounds of varying depth in both populations studied.