Peripheral fat loss, or lipoatrophy, has been reported as an emerging complication of long-term antiretroviral regimens, mainly when nucleoside analogues are included. However, lipoatrophy does not develop in the majority of nucleoside inhibitor-treated patients, leading to the investigation of factors other than drug effects alone as potential contributors to this complication. We conducted a retrospective cohort study study and analysis of repository plasma samples taken from HIV-infected patients being treated with their initial antiretroviral regimen. CD4 cell count and plasma tumor necrosis factor (TNF), soluble TNF receptors, and leptin levels were assessed and correlated with the development of lipoatrophy. The most significant treatment-related factor in this study of patients on their first drug regimen was duration of antiretroviral therapy, rather than type of nucleoside inhibitor treatment. No association was found between lipoatrophy and specific nucleoside inhibitors, including zidovudine and stavudine. A significant association between lipoatrophy was found for 2 nondrug risk factors: older age and lower pretherapy body mass index. Our results emphasize the need for keeping in mind the role of host factors in the generation of lipoatrophy.