Background: The lung is an important reservoir of human immunodeficiency virus (HIV). Individuals infected with HIV are more prone to pulmonary infections and chronic lung disorders. We hypothesized that comprehensively profiling the proteomic landscape of bronchoalveolar lavage fluid (BALF) in patients with HIV would provide insights into how this virus alters the lung milieu and contributes to pathogenesis of HIV-related lung diseases. Methods: BALF was obtained from five HIV-negative (HIV^-) and six asymptomatic HIV-positive (HIV⁺) subjects not on anti-retroviral therapy (ART). Each sample underwent shotgun proteomic analysis based on HPLC-tandem mass spectrometry. Differentially expressed proteins between the groups were identified using statistical methods based on spectral counting. Mechanisms of disease were explored using functional annotation to identify overlapping and distinct pathways enriched between the BALF proteome of HIV⁺ and HIV^- subjects. Results: We identified a total of 318 unique proteins in BALF of HIV^- and HIV⁺ subjects. Of these, 87 were differentially up or down-regulated between the two groups. Many of these differentially expressed proteins are known to interact with key HIV proteins. Functional analysis of differentially regulated proteins implicated down-regulation of immune responses in lungs of HIV⁺ patients. Conclusions: Combining shotgun proteomic analysis with computational methods demonstrated that the BALF proteome is significantly altered during HIV infection. We found that immunity-related pathways are under-represented in HIV+ patients. These findings implicate mechanisms whereby HIV invokes local immunosuppression in the lung and increases the susceptibility of HIV⁺ patients to develop a wide range of infectious and noninfectious pulmonary diseases.