Abstract: Coronary artery disease (CAD) is a complex disease with genetic and environmental determinants. Although a large number of genetic polymorphisms involved in the pathogenesis of atherosclerosis have been identified, there is still no evidence of a genetic association with CAD. As melatonin might play a role in the pathogenesis of atherosclerosis through its anti-inflammatory and antioxidant properties, we tested whether the expression of six single nucleotide polymorphisms (SNPs) of the melatonin receptor differs in acute myocardial infarction (AMI) patients with acute myocardial infarction (n = 300) compared with healthy age- and sex-matched controls (n = 250). Finally, only MEL1A receptor SNP rs28383653 was selected because of Hardy–Weinberg equilibrium (χ2 = 0.49). The distribution of genotype frequencies for this SNP showed that the unfavourable CT genotype was significantly more frequent in patients with AMI than in controls (4.5% versus 1.3%; P = 0.006). Multivariable analysis showed a significantly higher frequency of the unfavourable CT genotype in AMI patients with peripheral arteriopathy (28% versus 10%; P = 0.01). This finding suggests a synergism effect between the unfavourable genotype (CT) of the MELIA receptor SNP and the vascular disease in this subgroup of patients. To our knowledge, this is the first study to report an association between a genetic polymorphism of the melatonin receptor 1A and CAD.