The scavenger receptor class B type I (SR-BI) is a lipoprotein receptor that has been shown to be important in high density lipoprotein cholesterol (HDL-C) metabolism in mice. To determine its role in humans, we have characterized the human SR-BI gene and investigated its genetic variation in 489 white men and women. Five variants were demonstrated: 2 in introns (3 and 5) and 3 in exons (1, 8, and 11). Three variants at exons 1 and 8 and intron 5 with allele frequencies >0.1 were used to examine associations with lipid or anthropometric variables. The exon 1 variant was significantly (P<0.05) associated with increased HDL-C and lower low density lipoprotein cholesterol (LDL-C) values in men, but no associations were observed in women. The exon 8 variant was associated in women with lower LDL-C concentrations (3.05+/-0.98 mmol/L and 3.00+/-0.93 mmol/L for heterozygotes and homozygotes, respectively) compared with women homozygous for the common allele (3.39+/-1.09 mmol/L, P=0. 043). No associations for this variant were observed in men. Women carriers of the intron 5 variant showed a higher body mass index (23. 8+/-3.8 kg/m2, P=0.031) than those women homozygous for the common allele (22.4+/-3.4 kg/m2). Similar results were observed after haplotype analysis. Multiple regression analysis using HDL-C, LDL-C, and body mass index as dependent variables and age, sex, and each of the genetic variants as predictors also provided similar results. The associations found with both LDL-C and HDL-C suggest that SR-BI may play a role in the metabolism of both lipoprotein classes in humans.