P-selectin is a cellular adhesion molecule that may be involved in the development of atherosclerosis and its complications. We have previously identified thirteen polymorphisms of the P-selectin gene among which five were located in the coding region of the gene (S290N, N562D, V599L, T715P, T741T (A/G)). These polymorphisms were tested individually for association with myocardial infarction (MI) and only the T715P polymorphism was shown to be associated with MI. We here extend this work by performing a haplotype analysis which enables us to assess the consequences on the phenotype of the co-presence of several variants on the same chromosome. For this purpose, a new maximum likelihood method was developed for estimating simultaneously haplotype frequencies and haplotype-phenotype effects. While haplotypes defined by the polymorphisms located in the promoter region of the gene were unrelated to MI, those defined by the polymorphisms in the coding region were globally associated with MI in a sample of 582 cases and 630 controls from the Etude Cas-Témoin sur l'Infarctus du Myocarde. Detailed haplotype analysis confirmed the protective effect of the P715 allele but additionally revealed that the presence of two asparagine codons at sites S290N and N562D was associated with a higher risk of MI, consistenly in France and Northern Ireland, but only when they were carried by the same haplotype. This finding illustrates the complexity of the relationship between gene variability and disease and the necessity to explore in detail the polymorphisms of candidate genes.