The protective effect of prostaglandin D2 (PGD2) in ethanol-, HCl-, or NaCl-induced gastric mucosal injury was investigated. To clarify the mechanism, the gastric mucosal hemodynamics were also investigated using reflectance spectrophotometry and laser Doppler flowmetry in anesthetized rats. PGD2 administered orally significantly reduced the ethanol-induced mucosal injury. Although it did not reach any significance, PGD2 also reduced 0.6 N HCl-induced mucosal damage, and slightly reduced 25% NaCl-induced mucosal damage. Topical application of PGD2 did not affect gastric mucosal hemodynamics at steady state before the administration of necrotizing agent. However, PGD2 significantly improved the gastric mucosal microcirculatory congestion caused by ethanol, and partly improved 0.6 N HCl-induced ischemia. However, it did not improve the 25% NaCl-induced mucosal congestion. The results indicated that PGD2 had a protective effect in the ethanol-induced gastric mucosal injury through the improvement of gastric mucosal microcirculation. However, further investigations are needed to clarify the precise effect of PGD2 in 0.6 N HCl- or 25% NaCl-induced mucosal damage.