The current studies were designed to investigate the effect of calcium channel blockers on chemically induced gastric lesions in rats. Results of this study indicate that pretreatment of male F344 rats with the calcium channel blockers verapamil, diltiazem, or Mg2+ significantly protected against ethanol- and indomethacin-induced gastric lesions as demonstrated by gross and histopathologic evaluation. Treatment of rats with calcium channel blockers before ethanol or indomethacin administration resulted in a significant decline in the mean number of lesions per glandular stomach, the damaged area of the glandular stomach, and the severity of lesions. Calcium channel blockers also caused a significant decline in the incidence of indomethacin-induced gastric lesions, but had no effect on the incidence of ethanol-induced gastric lesions. These results offer the first evidence that calcium channel blockers may play an important role in the protection against chemically induced gastric lesions and thereby offer insight into the mechanism of gastric ulcer formation. It is speculated that this knowledge may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans.