<b><i>Background/Aims:</i></b> Gastrointestinal damage (GD) is commonly associated with the inhibition of cyclooxygenase (COX)-1, one of the two known COXs, by traditional non-steroidal anti-inflammatory drugs. More recent evidences have proven that GD is caused by the simultaneous inhibition of the two COXs. This study was designed to evaluate the effect of the selective COX-1 inhibition on gastric integrity. <b><i>Methods:</i></b> GD was evaluated in male CD1 mice. Drugs were administered by gastric gavage at a dose of 50 mg/kg (injection volume of 100 µl). Control mice received an equal volume of the vehicle (10% ethanol). Each mouse, in groups of at least 6 mice, received one dose/day for 5 days. <b><i>Results:</i></b> In Western blot analysis, COX-1 expression levels were found to be significantly reduced in mice treated with 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) in comparison to mice pretreated with aspirin (ASA), which exhibited higher levels of COX-1, thus confirming the high selectivity of P6 towards COX-1 enzyme inhibition. Mucosal sections obtained from ASA-treated mice showed breaks in the epithelial barrier and a marked alteration of foveolae and gastric glands, whereas stomachs isolated from mice sacrificed after 5 days of chronic administration of P6 (at a dose of up to 50 mg/kg/day) showed sporadic transient mucosal hyperemia and did not seem to display any significant gastric damage. <b><i>Conclusions:</i></b> The selective COX-1 inhibition by P6 does not cause gastric damage in mice but preserves mucosal integrity.