The effect of 2'-carboxymethoxy-4,4'-bis(3-methyl-2-butenyloxy)-chalcone (sofalcone, Solon) on 0.6N HCl-induced gastric lesions in the rat was studied. Sofalcone administered orally or intraperitoneally prevented the formation of gastric lesions induced by the necrotizing agent dose-dependently. Oral administration of sofalcone inhibited the aggravating effect of indometacin on the lesions induced by 0.6N HCl. Intraperitoneal administration of sofalcone also inhibited the aggravation of the lesions by indometacin treatment when it was given 30 min after the administration of sofalcone. This effect of sofalcone was not observed when indometacin was given 30 min before sofalcone. Simultaneous treatment with sofalcone and cimetidine inhibited the formation of the necrotic lesion synergistically. Carbenoxolone and cetraxate given orally protected the gastric mucosa against 0.6N HCl. Their protective effects were decreased when they were given intraperitoneally. These results suggested that the cytoprotective effect of sofalcone does not depend on the route of administration and that there are some interactions between cimetidine and sofalcone in their synergistic cytoprotective effects.