The increased longevity afforded by combination antiretroviral therapy in developed countries has led to an increased concern regarding senescence-related diseases in patients with human immunodeficiency virus (HIV) infection. Previous epidemiologic analyses have demonstrated an increased risk of chronic obstructive pulmonary disease, as well as a significant burden of respiratory symptoms in HIV-infected patients. We performed the St. George's Respiratory Questionnaire (SGRQ) in 199 HIV-positive men, and determined the predominant factors contributing to poor respiratory-related health status. In univariate analyses, worse SGRQ scores were associated with respiratory-related variables such as greater smoking pack-year history (p=0.028), lower forced expiratory volume in 1 second (FEV1) (p<0.001), and worse emphysema severity as quantified by computed tomographic imaging (p=0.017). In addition, HIV-specific variables, such as a history of plasma viral load >100,000 copies/mL (p=0.043), lower nadir CD4 cell count (p=0.040), and current CD4 cell count ≤350 cells/μL (p=0.005), as well as elevated levels of inflammatory markers, specifically plasma interleukin (IL)-6 (p=0.002) and alpha-1 antitrypsin (p=0.005) were also associated with worse SGRQ scores. In a multiple regression model, FEV1, current CD4 count ≤350 cells/μL, and IL-6 levels remained significant contributors to reduced respiratory-related health status. HIV disease activity as measured by HIV-related immunosuppression in conjunction with the triggering of key inflammatory pathways may be important determinants of worse respiratory health status among HIV-infected individuals. Limitations of this analysis include the absence of available echocardiograms, diffusion capacity and lung volume testing, and an all-male cohort due to the demographics of the clinic population.