To identify clinical factors associated with the incidence of HIV-1–associated lipoatrophy, HIV-1–infected patients in the HIV Outpatient Study (HOPS) were prospectively evaluated for clinical signs of lipoatrophy at two visits about 21 months apart. Development of lipoatrophy was analyzed in stratified and multivariate analyses for its relationship to immunologic, virologic, clinical, and drug treatment information for each patient. Of 337 patients with no lipoatrophy at Survey 1, 44 (13.1%) developed moderate or severe lipoatrophy between the two surveys. In multivariate analyses, significant risk factors for incident lipoatrophy were white race (OR = 5.2; 95% CI: 1.9–17.1;p = .003), CD4 T-lymphocyte count at Survey 2 less than 100 cells/mm3 (OR = 4.2; 95% CI: 1.3–13.1;p = .013), and body mass index (BMI) less than 24 kg/m2 (OR = 2.4; 95% CI: 1.1–5.4;p = .024). Analyses that controlled for the severity of HIV illness demonstrated no significant association with use of or time on any antiretroviral agent or class of agents and the development of lipoatrophy. Some host factors and factors associated with previous or current severity of HIV infection, especially CD4 T-lymphocyte cell count, appeared to have the strongest association with incidence of lipoatrophy.