Nelfinavir and other HIV protease inhibitors effectively suppress morbidity and mortality ill wHIV-infected patients. However. therapeutic use of HIV protease inhibitors has been temporally associated with the development of a lipodystrophy/insulin resistance syndrome and some evidence suggests that HIV protease inhibitors may be the causative agent. We report here that nelfinavir promotes loss of cytoplasmic triglyceride from fully differentiated adipocytes and inhibits preadipocyte differentiation at biologically relevant concentrations. Forced expression of the adipogenic transcription factor C/EBPalpha rescues some of the anti-adipogenic effects of nelfinavir. These results suggest that nelfinavir may mediate an anti-adipogenic effect by antagonizing expression of C/EBPalpha. (C) 2004 Elsevier Inc. All rights reserved.