The effect of topically applied aspirin or HCl, or both, on gastric mucosal blood flow was studied by in vivo microscopy in the rat. Ten minutes after the topical application of 20 mM aspirin in 50 mM HCl, red blood cell flow ceased and red blood cells were no longer present in the superficial mucosal microvessels in 76.8% +/- 7.7% of the microscopic field. Hydrochloric acid (50 mM) alone caused this effect in only 12.8% +/- 12.8% of the field, whereas 20 mM aspirin alone had no effect. During this microcirculatory change, white thrombi were observed flowing through mucosal microvessels. Later, mucosal hemorrhages developed in areas where flow had ceased. Study of the submucosal microcirculation suggested that high concentrations of HCl are responsible for thrombus formation and low concentrations of HCl for submucosal arteriolar constriction. These results suggest that aspirin-induced acid back-diffusion causes thrombus formation in mucosal microvessels and submucosal arteriolar constriction. These microcirculatory changes might play a causative role in the cessation of mucosal blood flow, mucosal injury, and focal hemorrhage.