Use of protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) has been associated with altered regional fat distribution, insulin resistance, and dyslipidemias. To assess how PI-based HAART affects adipocyte gene expression in male HIV-1-infected patients, reverse transcription- polymerase chain reaction was used to quantify messenger RNA expression of adipocyte transcription factors and adipocytokines in thigh and abdominal subcutaneous adipose tissue from male (1) HIV-1 seronegative subjects (control, n = 9), (2) asymptomatic treatment-naive HIV-1-infected patients (naive, n = 6), (3) HIV-1-infected patients who were receiving antiretroviral agents but never received PIs (PI naive, n = 5), (4) HIV-1-infected patients who were receiving PI-based HAART (PI, n = 7), and (5) HIV-1-infected patients who discontinued the PI component of their antiviral therapy more than 6 months before enrollment (past PI, n =7). In the PI group, the messenger RNA expression levels of the CCAAT/enhancer-binding protein α, leptin, and adiponectin (18%, P <. 01; 23%, P <. 05; and 13%, P <. 05, respectively) were significantly lower than the levels measured in the PI-naive group. These results are consistent with previous studies on the effects of PIs on cultured adipocytes. Prospective longitudinal studies of thigh fat adipose tissue gene expression could provide further insights on the pathogenesis of metabolic complications associated with PI-based HAART.