Patients with cardiovascular disease taking aspirin and some nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have increased vascular events. This study was conducted to compare the ex vivo antiplatelet effects of 6 commonly used NSAIDs and to determine whether these agents antagonize the effect of aspirin. Platelet function was assessed by Platelet Function Analyzer 100 closure time in normal subjects in a randomized, blinded, multiple-crossover study. Platelet function was measured 12 hours after the administration of each NSAID. The NSAID was then given 2 hours before aspirin 300 mg, and platelet function was reassessed 24 hours later. At 12 hours after the administration of naproxen and tiaprofenic acid, closure time was significantly prolonged, whereas the other NSAIDs did not cause significant prolongations. Compared with placebo plus aspirin, closure time was significantly reduced when ibuprofen, indomethacin, naproxen, or tiaprofenic acid was given before aspirin. In conclusion, ibuprofen, indomethacin, naproxen, and tiaprofenic acid all block the antiplatelet effect of aspirin. Sulindac and celecoxib did not demonstrate any significant antiplatelet effect or reduce the antiplatelet of aspirin and, therefore, of the NSAIDs evaluated may be the drugs of choice for patients requiring aspirin and NSAIDs.