Despite the best clinical practice, chronic nonhealing ulcers of the lower extremities present a significant challenge. Nitric oxide (NO) has been shown to play a significant role in biological functions including wound healing and as an antimicrobial agent in nonspecific immune response. Our goal was to study the effect of gaseous NO (gNO) administered directly to a two-year-old nonhealing chronic venous ulcer in a 55-year-old male presenting with a 30-year history of severe venous disease. gNO (200 ppm) was applied to the lower extremity using a delivery system connected to a "single patient use" plastic boot, at 1.0 L/min. The patient received an average of 8.1-h treatments for 14 consecutive nights. On day 0 the wound was malodorous and covered by bacterial biofilm with little healthy granulation tissue present. Following 3 days of gNO treatment, healthy granulation tissue was noted with absence of malodorous odor. At day 14, the ulcer was significantly reduced in size (p = 0.014) and almost completely reepithelialized. Day 10 post-treatment did not reveal any deterioration in healing. Six weeks later, the wound was 90% healed. At 26 weeks post gNO discontinuation, the ulcer was completely healed. This single case study demonstrated that gNO as a topical agent was well tolerated by the patient without any report of discomfort or side effect. The result of wound healing was very promising and warrants future exploration.