BACKGROUND: The cyclooxygenase-2 (COX-2) selective nonsteroidal antiinflammatory drugs (NSAIDs) celecoxib and rofecoxib (before its removal) are marketed as having fewer gastrointestinal (GI)-related complications than nonselective NSAIDs. However, adverse reaction data suggest that the use of COX-2 selective NSAIDs is associated with clinically significant GI events. OBJECTIVE: To assess whether patients receiving celecoxib and rofecoxib have a greater underlying disease burden than patients prescribed nonselective NSAIDs. METHODS: The study population consisted of members of 11 health plans, aged >34 years, with a pharmacy claim for celecoxib or rofecoxib or a nonselective NSAID dispensed between February 1, 1999, and July 31, 2001, who had been continuously enrolled for >364 days before the dispensing date. Celecoxib and rofecoxib patients were randomly selected without replacement from a pool of eligible users in each of the 30 months. Nonselective NSAID users were randomly chosen without replacement within each month on a 2:1 ratio to cases; they could be chosen in more than one month. Univariate analyses comparing 9000 cases and 18 000 controls were performed, followed by a multiple logistic regression analysis conditioned on time. RESULTS: Increasing age, treatment by a rheumatologist or an orthopedic specialist, treatment with a high number of different medications in the past year, treatment with oral corticosteroids in the past year, and having had a previous GI bleed increased the likelihood of receiving celecoxib or rofecoxib, whereas treatment with a high number of nonselective NSAID prescriptions in the past year decreased it. Treatment with a high number of different medications was a predictor of increased prevalence of underlying diabetes mellitus and cardiovascular disease. CONCLUSIONS: Patients having a greater underlying disease burden were more likely to receive COX-2 selective NSAIDs than nonselective ones. Paradoxically, patients at higher risk for cardiovascular disease were channeled toward treatment with COX-2 selective NSAIDs, many of which may confer an increased risk of acute myocardial infarction and other adverse cardiovascular outcomes.