New HIV therapies have significantly increased survival, but are associated with multiple metabolic changes, most of them related to the protease inhibitors (PIs). The objective of this study was to elucidate and compare morphological and metabolic alterations in HIV-infected antiretroviral-naive patients receiving two nucleosides plus the PI nelfinavir (NFV) or the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP). Forty-three patients (NFV, n = 20; NVP, n = 23) receiving 6-12 months of treatment were analyzed. Morphological changes were evaluated by bioelectrical impedance analysis, standard anthropometrics, and clinical examination. Serum total cholesterol (TC), low-density and high- density (HDL-c) lipoprotein cholesterol, triglycerides, glucose, and insulin were determined, among other metabolic parameters. No baseline differences were observed between groups. TC increased in both arms (NVP, 11%; NFV, 17%). HDL-c also increased in both groups, although more markedly in those receiving NVP (44% vs. 20%); on-treatment levels were also elevated (1.57 vs. 1.28 mmol/liter). As a consequence of these changes, the TC/HDL-c ratio dropped by 22% in the NVP arm and remained stable in the NFV group. With the use of NFV, the TC/HDL-c ratio and attendant cardiovascular risk did not change. In contrast, NVP offered benefits regarding lipid status, as manifested by enhanced HDL-c concentrations and decreased TC/HDL-c ratios. Inclusion of NVP should be considered when deciding upon antiretroviral regimens for patients at high coronary risk.