Increased body mass index (BMI) has been associated with adverse health outcomes but the effect of BMI on HIV immune markers over time post-HAART is not clearly established. Data were abstracted from 396 medical records at the Ryan White Clinic in South Carolina. All HIV-infected adults who were ≥18 years of age, diagnosed between 1997 and 2010, had weight and height measured within 3 months of diagnosis and had at least one follow-up visit within 6 months of diagnosis, were eligible. The mean CD4 count was calculated for each BMI category and mixed regression analyses was used to determine the association between BMI and CD4 count over time. The overall mean BMI was 27.4 kg/m2. Longitudinally, the mean CD4 count was 611.2 cells/mm3 for obese individuals, 598.1 cells/mm3 for overweight individuals and 550.5 cells/mm3 for normal weight individuals. When compared to the normal weight category, the obese category had significantly larger increases in CD4 count (5.5 cells/mm3, P < 0.001) versus the overweight category (−2.1 cells/mm3, P < 0.001). HIV-infected individuals who were obese at diagnosis had larger increases in CD4 counts over time when compared to overweight individuals at diagnosis. This suggests that providers should pay closer attention to weight at diagnosis to predict the response to treatment and disease trajectory.