Inflammatory reactions contribute to the development of arterial disease. We investigated the role of interleukin-4 (IL-4) in the development of myocardial infarction (MI) by genotyping patients with MI and control subjects for the -589C>T (rs2243250) single nucleotide polymorphism (SNP), which tags a functional haplotype of IL-4.Study of Myocardial Infarctions Leiden (SMILE) included 560 men with a first MI and 646 control subjects. The Valencia study included 305 patients with MI at T genotype was found [odds ratio (OR) 0.84; 95% CI 0.37-1.95 for -589TT and 0.82; 95% CI 0.62-1.07 for -589CT compared with -589CC]. In patients younger than 50 years, carriership of one or two -589T alleles was associated with a reduced risk of MI (OR 0.57: 95% CI 0.34-0.95). This result was replicated in the Valencia study, where carriers of one or two -589T alleles had a reduced risk of MI (OR 0.67: 95% CI 0.47-0.95), with a strong protective effect of the -598T allele in homozygous -589T (OR 0.33: 95% CI 0.10-1.05). In the control subjects of the Valencia study, the -589T allele was associated with reduced levels of F1+2.Our data indicate that the IL-4 haplotype tagged by the -589T allele reduces the risk of MI in young individuals.