We have conducted a crossover, randomized, double-blind dietary trial that tested the hypothesis that gender influences the response of plasma lipids, in particular high density lipoprotein (HDL) cholesterol, to dietary fat plus cholesterol. Twenty-six men and 25 women were matched for age, low density lipoprotein (LDL) cholesterol, triglyceride, and body mass index (BMI). After a 2-week baseline low-fat (27% of calories), low-cholesterol period, subjects were given two isocaloric liquid supplements for 3 weeks each, one containing 31 g fat (56% saturated) and 650 mg cholesterol, and the other fat free. The baseline HDL2 cholesterol level was significantly higher in women: 0.41 versus 0.26 mmol/l (p less than 0.01). Importantly, women also showed a greater rise in HDL2 cholesterol concentration with the fat/cholesterol supplement: 0.09 versus 0.03 mmol/l (p less than 0.01). The greater increment in women was related to their higher baseline HDL2 cholesterol levels. With the fat and cholesterol supplement, LDL cholesterol values rose from 3.76 to 4.04 mmol/l in women and from 3.77 to 4.13 mmol/l in men. The baseline LDL cholesterol value was found to account for about 35% of the variance in the rise in LDL cholesterol level with fat and cholesterol supplementation in both men and women less than 50 years. In men only, there was a significant effect of age: the change in LDL cholesterol with the fat/cholesterol supplement was 0.16 mmol/l in those less than 50 and 0.54 mmol/l in those greater than 50 years old (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)