The present study was to investigate the roles of cyclooxygenase-1 and -2 (COX-1 and COX-2) and prostaglandin (PG) on gastric mucosal integrity of partially sleep deprived (PSD) rats. A slowly moving drum was used to induce PSD. The PG levels in the gastric mucosa of PSD rats, with or without indomethacin or rofecoxib treatment, were determined. Exogenous prostaglandin E (PGE) analog, misoprostol, was administered to PSD rats to investigate the modulating effect of PG in indomethacin-induced gastric damage. It was observed that COX-1 mRNA and protein were up-regulated in the gastric mucosa of PSD rats. Selective COX-2 inhibition by rofecoxib failed to decrease mucosal PGE2 levels nor to affect mucosal integrity in both PSD and sleep undisturbed rats. However, indomethacin, a COX-1 preferential non-selective COX inhibitor, significantly reduced mucosal PGE2 content and produced more severe mucosal damage in PSD rats than in the controls. The deleterious effect of indomethacin on gastric mucosal integrity of PSD rats was significantly attenuated with the administration of misoprostol. These results suggest that PSD enhances COX-1 biosynthesis of gastroprotective PGE2 as an adaptive response of the stomach to stress. The administration of non-selective COX inhibitors to subjects with chronic sleep deprivation may induce more gastric damages.