Limited data prior to highly active antiretroviral therapy (HAART) suggested the possibility of an increased risk of COPD among those persons with HIV infection. We sought to determine whether HIV infection is associated with increased prevalence of COPD in the era of HAART. Prospective observational study of 1,014 HIV-positive and 713 HIV-negative men who were enrolled in the Veterans Aging Cohort 5 Site Study. COPD was determined by patient self-report and International Classification of Diseases, ninth revision (ICD-9), diagnostic codes. Cigarette smoking and injection drug use (IDU) were determined by self-report, and alcohol abuse was determined by ICD-9 diagnostic codes. Laboratory and pharmacy data were obtained from electronic medical records. The prevalence of COPD as determined by ICD-9 codes was 10% in HIV-positive subjects and 9% in HIV-negative subjects (p = 0.4), and as determined by patient self-report was 15% and 12%, respectively (p = 0.04). After adjusting for age, race/ethnicity, pack-years of smoking, IDU, and alcohol abuse, HIV infection was an independent risk factor for COPD. HIV-infected subjects were approximately 50 to 60% more likely to have COPD than HIV-negative subjects (by ICD-9 codes: odds ratio OR, 1.47; 95% confidence interval CI, 1.01 to 2.13; p = 0.04 ; by patient self-report: OR, 1.58; 95% CI, 1.14 to 2.18; p = 0.005). HIV infection was an independent risk factor for COPD, when determined either by ICD-9 codes or patient self-report. Health-care providers should be aware of the increased likelihood of COPD among their HIV-positive patients. The possibility that HIV infection increases susceptibility to and/or accelerates COPD deserves further investigation and has implications regarding the pathogenesis of COPD.