Studies associating the prothrombin 20210G>A (FII 20210A), factor V Leiden (FVL), and factor XIII Leu34 (FXIII-A Leu34) alleles with myocardial infarction (MI) have yielded conflicting results. Complicated gene-gene interactions, small sample sizes, and heterogeneous genetic and environmental backgrounds may contribute to opposing findings. Simultaneous analysis of multiple gene variants in a large sample size from a genetically isolated population may overcome these weaknesses. Genotyping was performed in 500 MI patients and 500 control subjects from the genetically isolated Newfoundland population to determine the prevalence of the FII 20210A, FVL, and FXIII-A Leu34 variants and their association with MI. Gene-gene interactions were also analyzed. The prevalence of the FII 20210A allele was higher in MI patients (3.2%) than in control subjects (1.0%; P =.015). The FII 20210A allele was also 5.6-fold higher in MI patients younger than 51 years than in age-matched control subjects (P =.04). FVL showed 3.9-fold higher prevalence in young patients than in patients older than 50 years (P =.004) and 2.7-fold higher than in age-matched control subjects (P =.007). Furthermore, the prevalence of combined carriers of the FXIII-A L34 and FII 20210A alleles was 12-fold higher in MI patients than in control subjects (P =.002) and with 92% penetrance. There was disequilibrium of the FXIII-A Leu34 allele to MI patients carrying the FII 20210A allele as a genetic background. Based on our data, we determined that (1) the FII 20210A allele is a risk factor for MI, possibly important for early onset; (2) FVL may predispose for early-onset MI; (3) the FXIII-A Leu34 allele predisposes for MI in males only; however, (4) interaction between the FII 20210A and FXIII-A Leu34 alleles forms a synergistic coeffect that strongly predisposes for MI, placing combined carriers at high risk for MI.