Diabetic foot ulcers (DFU) are common, difficult-to-treat, and prone to complications. A prospective, controlled study was conducted to: 1) examine the clinical efficacy of a pressurized topical oxygen therapy (TWO(2)) device in outpatients (N = 28) with severe DFU referred for care to a community wound care clinic and 2) assess ulcer reoccurrence rates after 24 months. Seventeen (17) patients received TWO(2) five times per week (60-minute treatment, pressure cycles between 5 and 50 mb) and 11 selected a silver-containing dressing changed at least twice per week (control). Patient demographics did not differ between treatment groups but wounds in the treatment group were more severe, perhaps as a result of selection bias. Ulcer duration was longer in the treatment (mean 6.1 months, SD 5.8) than in the control group (mean 3.2 months, SD 0.4) and mean baseline wound area was 4.1 cm2 (SD 4.3) in the treatment and 1.4 cm2 (SD 0.6) in the control group (P = 0.02). Fourteen (14) of 17 ulcers (82.4%) in the treatment group and five of 11 ulcers (45.5%) in the control group healed after a median of 56 and 93 days, respectively (P = 0.04). No adverse events were observed and there was no reoccurrence at the ulcer site after 24 months' follow-up in either group. Although the absence of randomization and blinding may have under- or overestimated the treatment effect of either group, the significant differences in treatment outcomes confirm the potential benefits of TWO(2) in the management of difficult-to-heal DFUs. Clinical efficacy and cost-effectiveness studies as well as studies to elucidate the mechanisms of action of TWO(2) are warranted.