OBJECTIVES: Hyperlactatemia is prevalent in HIV-infected patients on highly active antiretroviral therapy (HAART) and may be associated with depletion of mitochondrial DNA. However, the correlation between fasting lactate and mitochondrial DNA may be weak or absent, implicating that other factors e.g. glucose turnover may contribute to hyperlactatemia. METHODS: HIV-infected patients receiving HAART who had lipodystrophy (LIPO, n=18) or were without lipodystrophy (NONLIPO, n=18) were investigated. Insulin sensitivity (M-value), glucose oxidation rate (GOX) and fasting endogenous glucose production (EGP) were determined by hyperinsulinemic euglycemic clamp, indirect calorimetry and glucose tracer technique, respectively. RESULTS: Fasting p-lactate (median 1.2mmol/L; range 0.6-4.3, n=36) tended to be increased in LIPO (P=0.12); 6 patients (4 LIPO) had lactate >/=2.0mmol/L. Fasting lactate correlated inversely with M-value (P<0.001) and positively with fasting EGP (P<0.05) and fasting GOX (P<0.05), together explaining 51% (R(2), n=36) of the variation in fasting lactate. Lactate increased in NONLIPO (P<0.05) but not in LIPO (P>0.5) during clamp. Incremental (clamp minus fasting value) GOX (P<0.01) was decreased and incremental insulin (P<0.01) was increased in LIPO. CONCLUSIONS: Fasting EGP, GOX and insulin resistance may be major determinants of fasting lactate levels in HIV-infected patients on HAART. Insulin levels per se may not determine plasma lactate in such patients.