Hydrogen sulfide is an endogenous mediator that relaxes vascular smooth muscle, exhibits several antiinflammatory activities, and contributes to gastric mucosal defense. This study was performed to examine the role of hydrogen sulfide in the resolution of injury; specifically, the healing of gastric ulcers. Ulcers were induced in rats by serosal application of acetic acid. This elicited a marked increase in gastric expression of the two key enzymes in hydrogen sulfide synthesis (cystathionine-beta-synthase and cystathionine-gamma-lyase) and in hydrogen sulfide synthesis. Twice-daily treatment for a week with hydrogen sulfide donors significantly increased the extent of healing of gastric ulcers as compared to vehicle-treatment. Similar treatment with L-cysteine, a precursor for hydrogen sulfide, also accelerated healing of the ulcers, and the effect was abolished by cotreatment with an inhibitor of cystathionine-gamma-lyase. The beneficial effects of hydrogen sulfide on ulcer healing were not dependent on nitric oxide synthesis, nor did they appear to occur through activation of ATP-sensitive K+ channels. These results suggest that hydrogen sulfide is produced in the gastric mucosa in response to injury and acts to promote healing. The results further suggest that drugs releasing hydrogen sulfide could be employed to accelerate healing of gastric ulcers, and possibly of other wounds.