Genetic variation in the hepatic lipase (HL) gene (LIPC) promoter is an important determinant of HL activity in Caucasians. As HL activity is increased in patients with type 2 diabetes mellitus, we have investigated whether the -514 C-to-T polymorphism acted independently of type 2 diabetes to regulate HL activity. The frequency of this polymorphism and its effect on plasma HL activity and lipids were examined in 203 Chinese patients with type 2 diabetes and 205 controls. The frequency of the T allele was 0.343 and 0.376 in male and female diabetic patients, respectively, compared with 0.371 and 0.372 in male and female controls. The effect of LIPC genotype on HL activity was similar between men and women, and between diabetic patients and non-diabetic controls, with the lowest HL activity being found in those subjects with the TT genotype. On multivariate analysis, gender, LIPC genotype, the presence of type 2 diabetes and body mass index were independent predictors of HL activity, accounting for 22, 9, 5 and 3%, respectively, of the variance in HL activity (whole model adjusted R(2)=0.39, P<0.0001). The T allele was associated with higher high-density lipoprotein in the controls but not in the diabetic patients, and no associations were found between LIPC genotype and low-density lipoprotein subfractions in either groups. In conclusion, despite the higher frequency of the T allele in Chinese than in Caucasians, gender was the best predictor for HL activity, with LIPC gene polymorphism and type 2 diabetes making relatively smaller contributions to the variation in HL activity.