The need for antiretroviral therapy coupled with treatment of chronic co-morbidities places HIV-infected patients at risk for polypharmacy. However, few studies have described overall pill burden among HIV-infected patients. HIV-infected outpatients of the UNC Infectious Diseases Clinic were enrolled in this cross-sectional study. Subjects were contacted prior to a scheduled appointment and asked to bring all their medications to the visit. Daily total pill burden and medication type were recorded. 151 subjects were recruited: 76% male, 58% African American, 97% receiving antiretrovirals (ARVs). Median age was 48 (IRQ: 42-54) years. The median number of medications per subject was 8 (IQR: 6-11), and the median individual daily pill burden was 8 pills (IQR: 5-15): 3 pills (range: 2-5) for ARVs and 6 (range: 3-12.5) pills for non-ARVs. Duration of ART (per 2 years increase) and more than 3 co-morbidities was significantly associated with high pill burden (over 10 pills per day) with adjusted OR of 2.09 (95% CI, 1.14-3.84) and 8.04 (95% CI, 2.30-28.15), respectively. As patients with HIV age, strategies to reduce pill burden and number of medications will become increasingly critical to maintaining adherence, preventing medication errors, and serious drug-drug interactions.