Data on weight gain and the progression to overweight/obesity in HIV-infected persons during initial combination antiretroviral therapy (cART) are limited, and comparisons to the general population are inconclusive. Weight and body mass index (BMI) changes were studied in HIV-infected adults who remained on initial cART for 12 consecutive months and in an HIV-uninfected cohort receiving care at Duke University Medical Center between 1998 and 2008. Overweight/obesity was defined as BMI ≥25 kg/m(2). Variables were analyzed by Chi-square and Student's t-tests. Ninety-two HIV-infected persons (median age 38.2 years) met inclusion criteria. Weight and BMI increased during 12 months of cART (80.0 to 84.4 kg, p<0.0001; 26.4 to 27.9 kg/m(2), p<0.0001; respectively). Weight gain was greater in HIV-infected females compared to males (8.6 vs. 3.6 kg, p=0.04), in persons treated with protease inhibitor (PI)-based cART compared to non-PI-based cART (9.0 vs. 2.7 kg, p=0.001), and in persons with a pretreatment CD4 count <200 cells/mm(3) compared to ≥200 cells/mm(3) (8.9 vs. 0.3 kg, p<0.0001). Overweight/obesity prevalence increased from 52% to 66% during 12 months of initial cART, a 27% relative increase (p=0.002). HIV-infected persons had a lower prevalence of pretreatment overweight/obesity compared to 94 age-matched control subjects (52% vs. 91%, p<0.001); however, there was no change in weight (92.7 vs. 93.0 kg, p=0.5) or overweight/obesity prevalence (91% to 92%, p>0.9) during 12 months in the control cohort. Management should anticipate excess weight gain during the first year of cART in persons who are female, have a pretreatment CD4 <200 cells/mm(3), or will initiate PI-based cART.