Four common polymorphisms in the promoter of the hepatic lipase gene (LIPC) that are in almost complete linkage disequilibrium have been described in different ethnic groups. The T and A alleles at positions -514 and -250, respectively, were observed to be associated with decreased hepatic lipase (HL) activity and increased triglyceride content of HDL and LDL particles. We investigated whether these polymorphisms have any effect on transcriptional activity of the proximal promoter (-639 to +29) in transient transfection assays. We found that the promoter with T at position -514 had approximately 30% lower activity than the one with C at the same position (P < 0.0005) regardless of the genotype at position -250. In conclusion, these data indicate that the -514T allele may contribute significantly to decreased HL activity and the resultant increase in plasma levels of triglyceride-rich HDL(2) and large buoyant LDL particles. In addition, this promoter variant may explain the finding that its presence attenuates the increase in HL activity with increasing intra-abdominal fat in women.