Prostaglandins appear to play an important role in down-regulating intestinal inflammation and promoting repair of injury. In experimental colitis, inhibition of prostaglandin synthesis with nonsteroidal anti-inflammatory drugs (NSAID) leads to marked exacerbation of tissue injury. It has been suggested that the ability of chiral NSAID to inhibit prostaglandin synthesis is completely attributable to the S-enantiomer, while the R-enantiomer is a much weaker inhibitor. Thus, it is possible that R-enantiomers of chiral NSAID will have reduced intestinal toxicity and reduced ability to exacerbate colitis. In the present study, we compared R- and S-enantiomers of two chiral NSAID (flurbiprofen and etodolac) in terms of their ability to exacerbate colitis in the rat. We found that R-flurbiprofen and R-etodolac did not exacerbate colitis, in contrast to the S-enantiomers or racemates. The R-enantiomers also had significantly less inhibitory activity on prostaglandin synthase. Reduced biliary excretion of R-etodolac may have also contributed to the lack of detrimental effects in this model. The results support the hypothesis that prostaglandins play an essential role in down-regulating colonic inflammation and promoting repair.