AIMS:To explore further a recent finding that long-term users ofdiclofenacare at increasedriskofacutemyocardial infarction(AMI) similar to users of rofecoxib and celecoxib.METHODS:Using the General Practice Research Database, we conducted three separate nested case-control studies of three nonsteroidal anti-inflammatory drugs (NSAIDs) where use started after 1 January 1993--diclofenac, ibuprofen and naproxen. Cases of AMI were identified between 1 January 1993 and 31 December 2000. Relativerisk(RR) estimates for AMI inpatientswith nomajorclinicalrisk factorswere determined for each NSAID according to number of prescriptions received compared with one prescription. Results were adjusted for variables possibly related toriskof AMI.RESULTS:There was no material elevation of AMIriskaccording to the number of prescriptions for ibuprofen [RRs and 95% confidence intervals (CIs) 1.0 (0.6, 1.6) and 1.7 (0.9, 3.1) for use of 10-19 and 20+ prescriptions, respectively, compared with one prescription] or naproxen [RRs 1.0 (0.5, 2.2) and 2.0 (0.9, 4.5) for use of 10-19 and 20+ prescriptions, respectively]. However, a substantial increasedrisksimilar to that obtained in our prior study was found inpatientswho received >or=10 prescriptions fordiclofenac[RRs 1.9 (1.3, 2.7) and 2.0 (1.3, 3.0) for use of 10-19 and 20+ prescriptions, respectively].CONCLUSIONS:Extensive use ofdiclofenacsubstantially increases theriskof AMI. There is little suggestion of such an effect in users of ibuprofen and naproxen.