Recent studies suggest that decreased levels of high-density lipoprotein (HDL) may contribute to the risk of premature occlusive atherosclerosis in familial hypercholesterolemia (FH). To investigate further, we have analyzed the concentration as well as distribution of HDL cholesterol in relation to plasma triglycerides and their influence on ischaemic heart disease in FH subjects. The study was carried out in 71 men with heterozygous FH and 46 matched controls. FH subjects were relatively young with a mean age of 38 +/- 11 years. Tendon xanthomatas were observed in 57% of the subjects, whereas ischemic heart disease was identified in 33%. Compared to normals, the mean value of HDL cholesterol is significantly reduced by 21% in FH heterozygotes (42 +/- 12 v 33 +/- 9 mg/dL, P less than 0.001). The decrease in HDL cholesterol is highly correlated to the levels of plasma triglycerides (r = -0.50, P less than 0.001) and VLDL cholesterol (r = -0.53, P less than 0.001). Moreover, HDL cholesterol decrease is not associated with elevated levels of LDL cholesterol (r = -0.20, NS), which is the primary characteristic feature of FH subjects. However, HDL cholesterol decrease is weakly related to total plasma cholesterol concentration (r = -0.24, P less than 0.05). The body weight is also contributory to the reduction of HDL cholesterol (r = -0.42, P less than 0.01), probably due to its strong positive correlation to plasma triglycerides (r = +0.54, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)