Hepatic lipase (HL) hydrolyzes triglyceride and phospholipid in low and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively), and elevated HL activity is associated with small, dense atherogenic LDL particles and reduced HDL2-C. Elevated HL activity is associated with increasing age, male gender, high amounts of intraabdominal fat (IAF), and the HL gene (LIPC) promoter polymorphism (C nucleotide at -514). We investigated the mechanisms underlying the difference in HL activity between men (n = 44) and premenopausal women (n = 63). Men had significantly more IAF (144.5 +/- 80.9 vs. 66.5 +/- 43.2 cm(2), respectively; P < 0.001), higher HL activity (220.9 +/- 94.7 vs.129.9 +/- 53.5 nmol/mL.min; P < 0.001), more dense LDL (Rf, 0.277 +/- 0.032 vs. 0.300 +/- 0.024; P = 0.01), and less HDL2-C (0.19 +/- 0.10 vs. 0.32 +/- 0.16 mmol/L; P < 0.001) than women. After adjusting for IAF and the LIPC polymorphism, men continued to have higher (but attenuated) HL activity (194.5 +/- 80.4 vs.151.0 +/- 45.2, respectively; P = 0.007) and lower HDL2-C (0.23 +/- 0.11 vs. 0.29 +/- 0.14 mmol/L; P = 0.02) than women. Using multiple regression, HL activity remained independently related to IAF (P < 0.001), gender (P < 0.001), and the LIPC genotype (P < 0.001), with these factors accounting for 50% of the variance in HL activity. These data suggest that IAF is a major component of the gender difference in HL activity, but other gender-related differences, perhaps sex steroid hormones, also contribute to the higher HL activity seen in men compared with premenopausal women. The higher HL activity in men affects both LDL and HDL heterogeneity and may contribute to the gender difference in cardiovascular risk.