Previous investigations have shown that abnormalities in the postheparin plasma levels of the lipolytic enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are correlated with variations in plasma high-density lipoprotein cholesterol (HDL-C) levels. The present study was performed to determine correlations between the postheparin plasma activities of these two enzymes and HDL levels in a sizable number of subjects with low HDL-C levels. Two types of low-HDL subjects were investigated: 159 male subjects with low HDL-C (<40 mg/dL) and normal triglyceride (<250 mg/dL) levels (the low-HDL group) and 80 male subjects with low HDL-C (<40 mg/dL) and elevated triglyceride (>250 mg/dL) levels (the low-HDL/high-TG group). Postheparin plasma activities of LPL and HTGL were determined in these two groups, and these levels were compared with those obtained from 51 normolipidemic (normal-HDL) male subjects. Postheparin LPL activities were significantly lower in the low-HDL and low-HDL/high-TG groups (mean±SD, 9.9±2.9 and 10.4+3.0 mmol/h per liter, respectively;p<.001 for both) compared with the normal-HDL group (12.5±3.7 mmol/h per liter). Conversely, postheparin HTGL activities were significantly higher in the low-HDL and low-HDL/high-TG groups (39.3+16.2 and 44.4+16.7 mmol/h per liter, respectively;p<.001 for both) compared with the normal-HDL group (29.7±11.3 mmol/h per liter). Consequently, mean LPL/HTGL ratios were markedly lower in the two low-HDL groups compared with the normal-HDL group. Within each group, analysis revealed no specific relationships between the enzyme activities and potential modifying factors (cigarette smoking and β-adrenergic blocking agents). When subjects from each group who were neither smokers nor taking $-blockers were compared, HTGL activities, but not LPL activities, were significantly different for the low-HDL groups compared with the normal-HDL group. The results of this study suggest that high HTGL activity and low LPL activity are both important contributors to low HDL levels in both normotriglyceridemic and hypertriglyceridemic subjects. However, in the absence of potential modifying factors, high HTGL activity appears to be the major change in lipolytic enzymes associated with HDL levels.