Background: Diabetic foot ulcers are associated with significant morbidity. Conventional treatment modalities are often of limited success in promoting complete wound closure. The aim of the present study was to examine the efficacy of noninvasive ozone-oxygen therapy in the treatment of diabetic foot ulcers. Methods: Diabetes patients with a Wagner classification stage 2 or 3 ulcer or a stage 4 ulcer after debridement of at least 8 weeks in duration were included in this double-blind, randomized, placebo-controlled clinical trial. Patients received conventional treatment in combination with either ozone-oxygen treatment or sham treatments for 12 weeks, and after an additional 12 weeks, wound status was re-examined. Results: In total, 61 patients (62% male, 62.6±9.8 years old) participated in the study; 32 were randomized to ozone treatment, and 29 to placebo. The proportion of subjects with full wound closure did not differ significantly by treatment assignment (41% vs. 33%, P=0.34). Among the 34 subjects who completed the study per protocol (PP) (16 in the ozone group, 18 in the placebo group), a significantly higher rate of complete wound closure was observed in the ozone group (81% vs. 44%, P=0.03). Among PP patients with wound size ≤5 cm2, the rate of total wound closure was 100% versus 50% in the sham treatment group (P=0.006). A nonsignificant, 55.5% relative increase in healed wound area was detected in the ozone group versus the placebo group (4.2±4.9 cm2 vs. 2.7±1.5 cm2, P=0.23). Conclusions: Among PP patients, ozone treatment in addition to conventional treatment was superior to conventional treatment alone in promoting the complete healing of diabetic foot ulcers.