The roles of nucleoside analogues and protease inhibitors (PIs) in the development of metabolic complications and fat-distribution abnormalities associated with highly active antiretroviral therapy (HAART) are not well known. We performed an observational study in which efavirenz was substituted for a PI for 41 patients receiving HAART who had prolonged virus suppression, clinical signs of severe lipoatrophy, hyperlipidemia, and insulin resistance. Clinical follow-up was performed for 1 year. Virus suppression was maintained in most of the patients, and a significant increase in CD4(+) lymphocyte count was observed, but no change in lipid profile or insulin resistance was observed. Abdominal fat content did not change, and subcutaneous fat depletion was even more pronounced >1 year after the switch. We conclude that, for PI-treated patients who present with lipoatrophy, hyperlipidemia, and insulin resistance, substituting efavirenz for PIs can maintain virus suppression and immunologic response to HAART, but it does not improve the lipid profile or resolve insulin resistance or lipoatrophy.