The scavenger receptor class B type I (SR-BI) is a key component in the reverse cholesterol transport pathway. We have previously reported three common polymorphisms associated with plasma lipids and body mass index. We hypothesized that diabetic status may interact with these polymorphisms in determining plasma lipid concentrations and particle size. We evaluated this hypothesis in 2463 nondiabetic (49% men) and 187 diabetic (64% men) participants in the Framingham Study. SR-BI and APOE genotypes, anthropometric, clinical, biochemical, and lifestyle variables were determined. After multivariate adjustment, we found a consistent association between the exon 8 polymorphism and high-density lipoprotein cholesterol concentration and particle size. Interaction effects were not significant for exon 8 and intron 5 polymorphisms. However, we found statistically significant interactions between SR-BI exon 1 genotypes and type 2 diabetes, indicating that diabetic subjects with the less common allele (allele A) have lower lipid concentrations. For low-density lipoprotein cholesterol, the adjusted means (±se) were 3.31 ± 0.03 and 3.29 ± 0.04 mmol/liter for G/G and G/A or A/A in nondiabetics, respectively, compared with 3.19 ± 0.10 and 2.75 ± 0.01 mmol/liter for G/G and G/A or A/A in diabetics (P = 0.03 for interaction). Similar results were obtained for HDL₂-C. In conclusion, SR-BI gene variation modulates the lipid profile, particularly in type 2 diabetes, contributing to the metabolic abnormalities in these subjects.