OBJECTIVE: To investigate the risk of myocardial infarction (MI) with diclofenac, ibuprofen and naproxen, taking into account the exposure patterns. DESIGN: Retrospective cohort study using the General Practice Research Database. Setting. UK primary care. Subjects. Patients aged 40+ years prescribed a traditional nonsteroidal anti-inflammatory drug (NSAID). The control cohort was frequency matched by disease risk score. INTERVENTION: Observational comparisons of MI rates. RESULTS: The study included 729,294 NSAID users and 443,047 controls. The relative rate (RR) for MI increased with cumulative and daily dose (RR = 1.05 with 0-4 prior prescriptions and RR = 1.49 with 30+; RR = 1.05 with daily dose of or = 2400 mg per day; for diclofenac, the RR was 1.13 with or = 300 mg per day). Diclofenac users had higher risks of MI (RR = 1.21) than ibuprofen (RR = 1.04) or naproxen (RR = 1.03) users, but exposure varied between these drugs. Taking into account these exposure differences, it was found that the risk of MI was comparable in current and past long-term users. The patterns of hazard rates (i.e. absolute risks) of MI were similar in patients using ibuprofen, diclofenac or naproxen with similar history of NSAID use. There was no statistical difference between ibuprofen, diclofenac and ibuprofen in the linear trends for cumulative dose or daily dose. CONCLUSIONS: Long-term users of traditional NSAIDs have an increased risk of MI that is probably explained by the underlying disease severity. Most of the differences in MI risk between diclofenac, ibuprofen or naproxen may be explained by their varied use.