OBJECTIVE: To examine the risk of major cardiovascular disease associated with non-steroidal anti-inflammatory drugs (NSAIDs) in a large 'real-world' contemporary rheumatoid arthritis (RA) cohort. METHODS: A longitudinal cohort study was conducted with use of Danish nationwide individual-level registry data on inpatient and outpatient health care provision, pharmacotherapy and income during 1997-2009. 17 320 RA patients were identified and matched with 69 280 controls (4 : 1) by age and sex. NSAID-associated risk of major cardiovascular disease defined as the combined endpoint of myocardial infarction, stroke or cardiovascular mortality was assessed in multivariable survival models. RESULTS: During follow-up (median 4.9 years) 6283 events occurred. The cardiovascular risk associated with overall NSAID use was significantly lower in RA patients than in controls (HR 1.22 (95% CI 1.09 to 1.37) vs 1.51 (1.36 to 1.66), p<0.01). The pattern of lower NSAID-associated risk in RA patients was generally found with the individual NSAIDs investigated. While use of rofecoxib (HR 1.57 (1.16 to 2.12)) and diclofenac (HR 1.35 (1.11 to 1.64)) was associated with increased cardiovascular risk in RA patients, there was no significant risk increase associated with use of other NSAIDs in these patients. CONCLUSIONS: The cardiovascular risk associated with NSAID use in RA patients was modest and significantly lower than in non-RA individuals. Moreover, only a few of the individual NSAIDs were associated with increased cardiovascular risk. NSAID use should be assessed in the individual patient based on the indication for pain relief and risk factors for adverse effects, and not automatically be avoided due to concerns of severe cardiovascular outcomes alone.