Background. Human immunodeficiency virus (HIV) is readily detectable in the lungs of infected subjects and leads to an accumulation of CD8+ lymphocytes in the alveolar space. Although highly active antiretroviral therapy (HAART) is effective in reducing viremia, less is known about its effect on tissue compartments. The AIDS Clinical Trials Group Protocol 723 Team evaluated the effect of HAART on lung viral load and cellular constituents. Methods. Bronchoalveolar lavage (BAL) fluid and blood were collected before initiation of HAART and again at 4 and 24 weeks after initiation of therapy. The BAL cell differential was determined, lymphocyte phenotyping was performed, and acellular BAL fluid, plasma HIV RNA load, and BAL cell and peripheral blood mononuclear cell HIV RNA and DNA loads were measured. Results. HAART induced a rapid decrease in HIV that was detectable in acellular BAL fluid and a slower decrease in the HIV RNA and DNA loads in BAL cells. HAART was associated with a significant decrease in the absolute number and percentage of CD8+ alveolar lymphocytes. There was a significant correlation between residual BAL cell DNA at 24 weeks and the absolute number of CD4+ lymphocytes in the alveolar space. Conclusion. HAART is associated with a significant decrease in the pulmonary HIV burden and a return of alveolar cellular constituents to normal. © 2007 by the Infectious Diseases Society of America. All rights reserved.