The role of gaseous mediators NO and H2S and the cyclooxygenase/prostaglandins system in large intestinal mucosa was investigated in experiments on white rats under condition of experimental ulcerative colitis caused by introduction of acetic acid. Ulcerative colitis was accompanied by the formation of lesions of mucosal barrier of large intestine and the presence of ulcerative defects. The administration of H2S-releasing compound ATB-346 on the background of colitis significantly decreases the area of lesions as compared to naproxen or celecoxib action, that is the most probably caused by the action of H2S. Nonselective cyclooxygenase inhibition by naproxen was accompanied by the decrease of H2S concentration in blood serum and the level of gene Cbs expression in large intestinal mucosa, whereas under the condition of АТВ-346 action the above parameters were close to their normal values. Both naproxen and АТВ-346 decreased the level of gene Nos2 expression and activity of iNOS, which was sharply increased in colitis. Thus, the action of the naproxen derivative H2S releasing compound АТВ-346 is mainly caused by the action of hydrogen sulfide and its influence on іNOS system, and is manifested by a better cytoprotective effect as compared to naproxen action on the background of experimental ulcerative colitis.