The aim of the study was to investigate if the interaction between the coagulation factor 2 receptor (F2R) and the interleukin 6 (IL6) haplotypes modulates the risk of myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP). Seven SNPs at the F2R locus and three SNPs at the IL6 locus were genotyped. Haplotypes and haplotype pairs (IL6*F2R) were generated. A logistic regression analysis was performed to analyze the association of the haplotypes and haplotype pairs with the MI risk. Presence of an interaction between the two haplotypes in each haplotype pair was calculated using two different methods: the statistical, on a multiplicative scale, which includes the cross product of the two factors into the logistic regression model; the biological, on an additive scale, which evaluates the relative risk associated with the joint presence of both factors. The ratio between the observed and the predicted effect of the joint exposure, the synergy index (S), indicates the presence of a synergy (S>1) or of an antagonism (S<1). None of the haplotypes within the two loci was associated with the risk of MI. Out of 22 different haplotype pairs, the haplotype pair 17 GGG*ADGTCCT was associated with an increased risk of MI with an OR (95%CI) of 1.58 (1.05-2.41) (p = 0.02) in the crude and an OR of 1.72 (1.11-2.67) (p = 0.01) in the adjusted analysis. We observed the presence of an interaction on a multiplicative scale with an OR (95%CI) of 2.24 (1.27-3.95) (p = 0.005) and a slight interactive effect between the two haplotypes on an additive scale with an OR (95%CI) of 1.56 (1.02-2.37) (p = 0.03) and S of 1.66 (0.89-31). In conclusion, our results support the hypothesis that the interaction between these two functionally related genes may influence the risk of MI and suggest new mechanisms involved in the genetic susceptibility to MI.