Lipoprotein lipase degrades triglycerides in plasma and as a by-product produces HDL particles. Genetic variation in lipoprotein lipase may therefore affect cardiovascular risk. We tested 9214 men and women from a general population sample and 948 patients with ischaemic heart disease for the Asn291Ser substitution in lipoprotein lipase. The allele frequency in the general population was 0.024 and 0.026 for women and men, respectively. In comparison with non-carriers, female heterozygous probands had increased plasma triglycerides (delta = 0.23 mmol/L), while HDL cholesterol was reduced in both female and male carriers (delta = 0.18 mmol/L and delta = 0.11 mmol/L, respectively). A similar phenotype was found in six homozygous carriers. On multiple logistic regression analysis, plasma triglycerides and HDL cholesterol were independent predictors of ischaemic heart disease in both genders. On univariate analysis, odds ratios for ischaemic heart disease in probands were 1.89 in women (95% confidence interval: 1.19-3.01) and 0.90 (0.62-1.31) in men, and on multivariate analysis 1.98 (1.11-3.53) in women and 1.02 (0.65-1.60) in men. This study demonstrates that a single common mutation in the lipoprotein lipase gene is associated with elevated plasma triglycerides and reduced HDL cholesterol levels, whereby carriers, in particular women, seem to be predisposed to ischaemic heart disease. It cannot be excluded, however, that male carriers of this substitution may represent a subset of low-HDL individuals without raised triglycerides, not predisposed to ischaemic heart disease.