The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in platelet aggregation. Recent data suggest that the Pl(A2) polymorphism of GPIIIa may be associated with an increased risk for cardiovascular disease. However, it is unknown if there is any association between this polymorphism and platelet reactivity. We determined GP IlIa genotype and platelet reactivity phenotype data in 1422 subjects from the Framingham Offspring Study. Genotyping was performed using PCR-based restriction fragment length polymorphism analysis. Platelet aggregability was evaluated by the Born method. The threshold concentrations of epinephrine and ADP were determined. Allele frequencies of Pl(A1) and Pl(A2) were 0.84 and 0.16, respectively. The presence of 1 or 2 pl(A2) alleles was associated with increased platelet aggregability as indicated by incrementally lower threshold concentrations for epinephrine and ADP. For epinephrine, the mean concentrations were 0.9 μmol/L (0.9 to 1.0) for homozygous Pl(A1), 0.7 mmol/L (0.7 to 0.9) for the heterozygous Pl(A1)/Pl(A2), and 0.6 μmol/L (0.4 to 1.0) for homozygous Pl(A2) individuals, P=0.009. The increase in aggregability induced by epinephrine remained highly significant (P=0.007) after adjustment for covariates. For ADP-induced aggregation, the respective mean concentrations were 3.1 μmol/L (3.0 to 3.2), 3.0 μmol/L (2.9 to 3.2), and 2.8 μmol/L (2.4 to 3.3); P=0.19 after adjustment for covariates. Our findings indicate that molecular variants of the gene encoding GP IIIa play a role in platelet reactivity in vitro. Our observations are compatible with and provide an explanation for the reported association of the Pl(A2) allotype with increased risk for cardiovascular disease.