The metabolism of free fatty acids (FFA) is altered in two common atherosclerosis-promoting disorders: familial combined hyperlipidemia (FCHL) and insulin resistance syndrome (IRS). It has been suggested that these two conditions may have a common etiology. The enzymes lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) are rate-limiting steps for the turnover of fatty acids in adipose tissue, because they hydrolyze extracellular triglycerides in lipoproteins (LPL) and intracellular triglycerides in adipocytes (HSL). The present study was undertaken to simultaneously determine the activities of LPL and HSL in subcutaneous adipose tissue from male patients with FCHL and IRS. LPL and HSL activity was investigated in 10 nonobese FCHL patients and compared with 10 matched healthy nonobese subjects, and in 8 essentially normolipidemic IRS patients (who did not have overt diabetes mellitus) and compared with 9 nonobese matched control subjects. LPL activity was 43% lower in patients with IRS (P < .0005), as compared with control subjects, but HSL activity was not significantly different in the two groups, On the other hand, HSL activity was decreased by 45% in FCHL patients (P < .01), as compared with control subjects, but LPL activity was not significantly different in FCHL patients and the control group. In conclusion, triglyceride metabolism in adipose tissue is altered in both FCHL and IRS. However, the abnormalities observed involve impaired function of LPL in IRS and impaired function of HSL in FCHL, suggesting separate etiologies for the altered lipolysis in these conditions, at least in male subjects.