Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has been implicated in dyslipidemia, peripheral insulin resistance, and abnormal adipose tissue deposition in HIV/AIDS. In vitro evidence indicates that some PIs reduce adipocyte lipoprotein (LPL) and hepatic lipase (HL) expression and activities. We examined whether LPL and HL activities are reduced in HIV-infected patients with dyslipidemia. Fasting serum lipids, glucoregulatory hormones, post-heparin LPL and HL activities, as well as whole-body and regional adiposity were measured in: 19 HIV-seronegative controls, 9 HIV+ patients naive to all anti-HIV medications, 9 HIV+ patients naive to PI's, 9 HIV+ patients with prior PI experience but not currently receiving PIs, and 47 HIV+ patients receiving PI-HAART. The PI-HAART group had low LPL and HL activities. However, multiple linear regression analysis indicated that low post-heparin LPL activity only partially contributed to HIV-dyslipidemia. Central adiposity and high C-peptide levels (an indicator of high insulin secretion) were stronger predictors of HIV-dyslipidemia. Low LPL and HL activities, by themselves, were insufficient to explain HIV-dyslipidemia because the PI-naive group had low LPL and HL activities, but had normal adiposity, C-peptide levels and serum lipid and lipoprotein levels. HDL-cholesterol was lower in PI-HAART and PI naive groups than seronegative controls, and directly associated with LPL activity. These findings suggest that HIV-dyslipidemia is primarily mediated by factors that influence triglyceride and lipoprotein synthesis (eg., central adiposity and hyperinsulinemia), and only partially mediated by factors that influence triglyceride clearance (eg., lipase activity).