A number of studies have evaluated the effect of the -514C/T polymorphism of the hepatic lipase (HL) gene on concentration and composition of the plasma lipoproteins. However, the effect of this polymorphism on the response to hypolipaemic treatment has not been addressed. We evaluated the effect of this polymorphism on baseline lipids and lipoproteins and their response to treatment comprising 20mg/day pravastatin for 3 months. The study was multi-centred, prospective and interventional in 236 hypercholesterolaemic subjects (mean age 57.3 years; 45% males) from 21 Primary Health-care Centres. The lipid and genotype measurements were conducted centrally. The genotype distribution was 60.2% homozygous for the C allele and 36.0% heterozygous. No significant differences in baseline lipid concentrations between the genotypes were observed, except that carriers of the T allele had higher concentrations of triglycerides (p=0.021). Post-pravastatin, concentrations of HDL-C increased by 6.9% (95% CI: 2.9-10.8%) in those carrying the T allele with almost no change (0.8%) in the CC genotypes (95% CI: -2.3-4.0%) (p=0.019). The significance remained (p=0.014) following adjustment for other confounding factors (age, basal HDL-cholesterol, LDL-cholesterol and triglycerides). We conclude that the -514C/T polymorphism modulates significantly the HDL-C response to pravastatin, irrespective of the baseline lipoprotein concentrations.