BACKGROUND: Gene-nutrient interactions affecting hepatic lipase (HL) activity may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. OBJECTIVE: We determined the associations of dietary fat intake with postheparin HL activity and the possible modifying effect of the HL -480C-->T polymorphism on these associations. DESIGN: Subjects were recruited from participants in the 2000-2001 follow-up examination of the Hoorn Study. HL activity was determined in postheparin plasma in a sample of 211 men and 218 women aged 60-87 y. Information about dietary intake of the participants was obtained with a validated food-frequency questionnaire. Linear regression was performed, adjusted for age. RESULTS: Total dietary fat was positively associated with HL activity (standardized beta: 0.11; 95% CI: 0.02, 0.21), and this association was also seen for saturated fat (0.10; 0.01, 0.20) and monounsaturated fatty acid (0.10; 0.01, 0.19). We observed a significant interaction of the HL polymorphism with the relation between total fat intake and HL activity. The association of total fat with HL activity was stronger in subjects with CT (0.27; 0.11, 0.43) and TT (0.39; -0.22, 1.00) genotypes than in subjects with the CC genotype (0.06; -0.06, 0.18; P for interaction < 0.10). The interaction remained statistically significant in models that included age, sex, carbohydrate and protein intakes, and insulin or body mass index. CONCLUSIONS: Higher intakes of total and saturated fat were positively associated with higher HL activity. In addition, the observed association of total fat with HL activity was modified by the HL-480C-->T polymorphism, after adjustment for age, sex, carbohydrate and protein intakes, and insulin or body mass index.