A multicenter, phase 4, randomized, comparative-efficacy study in subjects with lower extremity wounds was carried out to compare wound closure rates, for a single-use negative pressure wound therapy (s-NPWT) versus traditional NPWT (t-NPWT) systems over a 12-week treatment period. From the initial population of patients with diabetic foot ulcers (DFU) and venous leg ulcers (VLU), we analyzed a subgroup of patients with diabetes mellitus and leg and foot ulcers (either DFUs or VLUs in diabetics), termed, the diabetic lower extremity ulcers (DLEU). In the DLEU group, there were 95 patients in intention-to-treat (ITT) and 61 patients in per protocol (PP) populations, respectively. We found a significant difference in favor of s-NPWT over t-NPWT in the confirmed wound closures at 12 weeks both in ITT (p < 0.001) and PP populations (p = 0.017). Significantly higher wound closure rates in s-NPWT group suggest that s-NPWT should be preferred NPWT option for DLEU.