CS-706 is a novel cyclooxygenase-2 (COX-2) inhibitor with potent analgesic, anti-inflammatory, and antitumor properties in animal models. This one-week, multicenter study was undertaken to assess the safety and tolerability of CS-706 and to compare the effects of CS-706 versus naproxen on acute gastrointestinal (GI) mucosal injury. Healthy men and women (n=160) without evidence of underlying gastroduodenal lesions were randomized to placebo, 100 mg CS-706 once daily, 200 mg CS-706 once daily, or 500 mg naproxen twice daily, administered for 7 days. On Day 8, subjects underwent a posttreatment upper GI endoscopy to assess development of gastroduodenal petechiae, erosions, and ulcers. Inhibition of COX-1 and COX-2 activity over the 24-hr postdose interval on Day 7 was determined in 48 subjects (12 per treatment group). CS-706 was safe and well tolerated. The extent of upper GI mucosal injury for both CS-706 dose groups was statistically significantly less than that for naproxen (P < 0.001) and was similar to placebo (P=0.615 and P=0.115 for 100 and 200 mg CS-706, respectively). No subject in placebo or either CS-706 treatment group had gastroduodenal ulcers, compared with 11 (28.2%) subjects treated with naproxen (P < 0.001). Both doses of CS-706 inhibited COX-2 activity to a similar extent as naproxen, whereas neither dose of CS-706 showed meaningful inhibition of platelet COX-1. In contrast, naproxen nearly completely inhibited COX-1 over the dosing interval. We conclude that CS-706, dosed up to 200 mg once daily, has an acute, upper GI toxicity profile similar to that of placebo and significantly superior to that of naproxen.