Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin synthesis by inhibiting cyclo-oxygenase 1 (COX-1) and/or cyclo-oxygenase 2 (COX-2). Different groups of NSAIDs, defined by their action on either COX-1 or COX-2, have been developed. Whether intestinal toxicity of preferential or selective COX-2 inhibitors is reduced compared with that of standard NSAIDs is controversial. We report the cases of two patients with self-limited colitis induced by preferential COX-2. We discuss the mechanisms of intestinal toxic effects of COX-2 preferential inhibitors from endoscopic and histological features of colitis.