Background: The success of antiretroviral therapy (ART) has led to dramatic changes in causes of morbidity and mortality in HIV-infected individuals. As chronic disease rates have increased in HIV-positive populations, modifiable risk factors such as obesity have increased in importance. Our objective was to evaluate factors associated with weight change among patients receiving ART. Methods: ART-naive patients initiating therapy at the University of Alabama, Birmingham 1917 HIV/AIDS Clinic from 2000 to 2008 were included. Body mass index (BMI) was categorized as: underweight (<18.5), normal weight (18.5-24.9), overweight (25-29.9) and obese (≥30). Linear regression models were used to evaluate overall change in BMI and factors associated with increased BMI category 24 months following ART initiation. Results: Among 681 patients, the mean baseline BMI was 25.4 ±6.1; 44% of patients were overweight/obese. At 24 months, 20% of patients moved from normal to overweight/obese or from overweight to obese BMI categories. Greater increases in BMI were observed in patients with baseline CD4+ T-cell counts <50 cells/ml (3.4 ±4.1; P<0.01) and in those on boosted protease inhibitors (2.5 ±4.1; P=0.01), but did not account for all of the variations observed in weight change. Conclusions: The findings that almost one-half of patients were overweight or obese at ART initiation and that 1 in 5 patients moved to a deleterious BMI category within 2 years of ART initiation are alarming. ART therapy provides only a modest contribution to weight gain in patients. Obesity represents a highly prevalent condition in patients with HIV infection and an important target for intervention. ©2012 International Medical Press.