The T allele at position -260 of the CD14 lipopolysaccharide receptor gene (CD14) has recently been hypothesized to be a risk factor for myocardial infarction (MI). However, no prospective data relating this polymorphism to risk of future MI are available. In the physicians' health study (PHS), 14916 apparently healthy men were followed over a 12-year period for incident MI. Employing a nested case-control study design, the CD14 C(-260)T polymorphism was evaluated among 387 study participants who developed MI (cases) and among an equal number of age- and smoking-matched study participants who remained free of vascular diseases during follow-up (controls). All observed genotype frequencies were in Hardy-Weinberg equilibrium. However, the allele and genotype distributions of the CD14 polymorphism were similar among cases and controls, both in the total cohort and in all subgroups evaluated. Furthermore, no evidence of association was observed assuming additive, dominant, or recessive mode of inheritance. For example, the relative risk of future MI in a comparison of homozygous mutants to homozygous wild types was 1.00 (95% CI=0.7-1.5; P=0.9). In this large prospective study, the CD14 C(-260)T gene polymorphism was not associated with risks of future MI. Thus, in contrast to prior studies, these data indicate that screening for CD14 C(-260)T genotypes is unlikely to be a useful tool for risk assessment.