Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors are widely used in patients with rheumatoid arthritis. Aspirin has the largest and most persuasive body of randomized trial evidence to support its use in secondary prevention for cardiovascular disease (CVD) and primary prevention for myocardial infarction. There is, however, a possible deleterious interaction between aspirin and NSAIDs on CVD that requires further research. Aspirin, NSAIDs, and to a lesser extent COX-2 inhibitors are associated with increased gastrointestinal side effects and bleeding, alone and in combination. The more widespread and appropriate use of aspirin in patients with rheumatoid arthritis will avoid many premature deaths in secondary prevention for CVD and first myocardial infarctions in primary prevention.