Exogenous prostaglandins inhibit visible gastric mucosal lesions produced by both absolute ethanol and cold restraint in the rat. Pretreatment with "mild irritants" significantly reduces the magnitude of ethanol-induced lesions presumably by stimulating endogenous prostanoid production. The effect of mild irritant pretreatment on cold restraint-induced lesion formation has not been previously reported. This study was designed to compare the protective effect of pretreatment with two "mild irritants," 4% NaCl and 0.35 M HCl, and the synthetic prostanoid, 16,16 dimethyl PGE2(16,16-dm PGE2), on lesions produced by cold restraint or absolute ethanol. Pretreatment with both mild irritants produced complete visible protection against ethanol-induced injury but had variable effects against cold restraint-induced injury. Whereas 5 micrograms/kg 16,16-dmPGE2 provided complete visible protection against ethanol-induced injury, 20 micrograms/kg 16,16-dmPGE2 was required for complete visible protection against cold restraint-induced injury. We conclude that prostaglandin requirements for protection against cold restraint injury are greater than for protection against ethanol-induced gastric mucosal injury.