It has been hypothesized that cyclooxygenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and lack of an effect on platelet thromboxane A(2) production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (< or =325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxygenase 2 specific inhibitors on the CV system.