To further understand the factors involved in the regulation of high plasma triglyceride (TG) or low plasma high density lipoprotein cholesterol (HDL-C) levels, three groups of male subjects (normal TG with low HDL-C levels, high TG with normal HDL-C levels, and high TG with low HDL-C levels) were compared with a sample of normolipemic men with normal TG and HDL-C plasma levels. Mean age was 34 years (range, 20-42 years), and none of the subjects had plasma TG levels >4.0 mmol/1 or familial hypercholesterolemia. Both groups of subjects with high TG levels had a higher body mass index, waist circumference, waist-to-hip circumferences ratio, and a higher ratio of abdominal to femoral adipose tissue areas as measured by computed tomography when compared with normolipemic control subjects. However, during an oral glucose tolerance test only high TG-low HDL-C men had fasting hyperinsulinemia and higher plasma insulin levels compared with normolipemic subjects. In addition, the high TG-low HDL-C group showed reduced HDL apoprotein (apo) A-I levels and a low HDL2-C/HDLrC ratio. These changes were observed along with a nonsignificant trend for a lower plasma postheparin lipoprotein lipase activity. However, among subjects with high TG and normal HDL-C levels, no evidence of insulin resistance or of a reduction in postheparin lipoprotein lipase activity was observed, suggesting that the high plasma TG levels could be attributed to an increased production of apo B-containing lipoproteins, as high plasma apo B and low density lipoprotein (LDL)-apo B levels were observed in this group. In addition, HDL-apo A-I levels measured in the high TG-normal HDL-C group were similar to normolipemic control subjects. Finally, in men with normal plasma TG and low HDL-C levels, no evidence of insulin resistance was noted, nor was there any sign of reduction in plasma postheparin lipoprotein lipase activity. However, HDL 2 -C, HDL,-C, and HDL-apo A-I levels were reduced, suggesting altered synthesis or catabolism of apo A-I. A nonsignificant trend for increased hepatic TG lipase activity was also observed in both groups with low HDL-C levels. These results provide further support for the presence of metabolic heterogeneity underlying high plasma TG or low HDL-C concentrations in men.