Twelve men and thirteen women with hypercholesterolaemia participated in a 20-week controlled cross-over trial to assess the interaction between dietary fat intake, gender and an HMGCoA reductase inhibitor, simvastatin. Subjects were matched for total cholesterol, age, body mass index (BMI) and plasma triglyceride. Gender-drug interactions were noted with men demonstrating only a 27% fall in LDL cholesterol with simvastatin when consuming a high fat (40% energy) diet compared to women with a 35% fall. In men, the lowest LDL/HDL ratio was achieved with simvastatin on a low fat diet (22% energy). Gender differences in the effect of simvastatin on HDL were confined to HDL3 cholesterol, although the drug raised HDL2 in both sexes on the low fat diet. Simvastatin was responsible for an 11% increase in HDL3 cholesterol in men particularly when on a low fat diet but did not affect HDL3 in women. An important diet-drug interaction was seen in triglyceride response, with a lowering of 17%-20% only when subjects were on a low fat diet. There was a gender difference in response to dietary fat change with men demonstrating a 19% decrease in triglycerides with dietary fat reduction while on simvastatin, whereas women showed a 9% increase which did not reach significance. Men also responded more favourably to dietary fat reduction with at least two-fold greater falls in plasma cholesterol than was seen in women.(ABSTRACT TRUNCATED AT 250 WORDS)