Recently, we localized the Human Poliovirus Receptor Related 2 Gene (PRR2) 17kb centromeric to the gene for apolipoprotein E (APOE). Common polymorphisms in the latter have been found, in some studies, to be related to coronary heart disease (CHD) but the PRR2 gene has not been studied in this context. Here, we examined relationships between a PRR2 Sau96I (A/G) polymorphism, the epsilon2, 3 and 4 alleles of APOE and CHD.Consecutive Caucasian patients (n = 640) < 50 years with angiographically documented coronary obstructive disease and/or with unequivocal myocardial infarction were compared with 624 control subjects, aged 30-50 years, randomly selected from the community and without a history of CHD.An excess of PRR2-A homozygotes was observed in cases (20% vs. 15%; OR 1.4, CI 1.04-1.86, P = 0.026) particularly in those with single vessel disease (OR 1.7, CI 1.2-2.4, P <0.01). The A allele was in linkage disequilibrium with the epsilon4 allele and the G allele with the epsilon2. Overrepresentation of the A allele and underrepresentation of the G allele in the CHD group did not reach significance (P = 0.054). While the epsilon2 allele was underrepresented in the CHD group (OR 0.64, CI 0.46-0.89, P = 0.009), the epsilon4 allele was not significantly overrepresented.The relationship between the PRR2 Sau96I (A/G) polymorphism and early onset coronary artery disease may be due to linkage disequilibrium with the APOE gene and underrepresentation, or a protective effect, of the epsilon2 allele. Alternatively, since A allele homozygosity is particularly overrepresented, the relationship could be more direct, perhaps through a viral association.