Aims To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors. Methods A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n= 460) were hospitalized with acute coronary syndrome (ACS). Controls (n= 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real-time polymerase chain reaction using allele-specific probes RESULTS Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the 'low risk' haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the 'high risk' haplotype (one or two copies of GT). CONCLUSIONS We found little evidence of a gene/drug interaction. We found a statistically non-significant trend toward a lower risk of coronary events with NSAIDs in the presence of the 'low risk' haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.