In the last year, several studies have reported conflicting results concerning an association between the PI(A2) allele of the PI(A1/A2) polymorphism of platelet glycoprotein IIIa and the risk of myocardial infarction. In the present study, we analyzed the hypothesis of whether glycoprotein IIIa genotypes have any association with lipids and lipoproteins as classical cardiovascular risk factors. Smoking, associated with changes in triglyceride-rich lipoprotein (TRL) concentrations and with both hypercoagulability and reduced fibrinolysis, was also analyzed as an environmental factor. Blood samples were obtained from 170 subjects (83 men and 87 women; mean age, 57 years; SD 15) recruited by random sampling from the census of Girona, Spain. Subjects were classified as current smokers (n=41) and nonsmokers or exsmokers (n=129). Whereas no differences were found in lipid and lipoprotein concentrations between smokers and nonsmokers in subjects with the PI(A1/A1) genotype, smokers with the PI(A1/A2) or PI(A2/A2) genotypes showed significantly higher triglyceride and very-low-density lipoprotein (VLDL) triglyceride concentrations than nonsmokers or exsmokers with the same genotypes. Similarly, the VLDL triglyceride/HDL cholesterol ratio was significantly different in subjects with the PI(A1/A2) or PI(A2/A2) genotypes stratified according to smoking status. Further analysis revealed a significant interaction between smoking and genotype when those homozygous for the allele PI(A1) were compared with one or two PI(A2) alleles for the three lipidic parameters. The observed effects appear to show links between smoking, triglyceride metabolism, and a glycoprotein involved in platelet aggregation. It is likely that the pI(A) polymorphism is in linkage disequilibrium with other functional mutations that might influence triglyceride metabolism under some environmental factors such as smoking. This finding may provide a new perspective in the complex relationship between glycoprotein IIIa gene, environment, and their interactions.