Background. Health care expenditures for persons infected with human immunodeficiency virus (HIV) in the United State determined on the basis of actual health care use have not been reported in the era of highly active antiretroviral therapy. Methods. Patients receiving primary care at the University of Alabama at Birmingham HIV clinic were included in the study. All encounters (except emergency room visits) that occurred within the University of Alabama at Birmingham Hospital System from 1 March 2000 to 1 March 2001 were analyzed. Medication expenditures were determined on the basis of 2001 average wholesale price. Hospitalization expenditures were determined on the basis of 2001 Medicare diagnostic related group reimbursement rates. Clinic expenditures were determined on the basis of 2001 Medicare current procedural terminology reimbursement rates. Results. Among the 635 patients, total annual expenditures for patients with CD4+ cell counts <50 cells/μL ($36,533 per patient) were 2.6-times greater than total annual expenditures for patients with CD4+ cell counts ≥350 cells/μL ($13,885 per patient), primarily because of increased expenditures for nonantiretroviral medication and hospitalization. Expenditures for highly active antiretroviral therapy were relatively constant at ∼$10,500 per patient per year across CD4+ cell count strata. Outpatient expenditures were $1558 per patient per year; however, the clinic and physician component of these expenditures represented only $359 per patient per year, or 2% of annual expenses. Health care expenditures for patients with HIV infection increased substantially for those with more-advanced disease and were driven predominantly by medication costs (which accounted for 71%-84% of annual expenses). Conclusions. Physician reimbursements, even with 100% billing and collections, are inadequate to support the activities of most clinics providing HIV care. These findings have important implications for the continued support of HIV treatment programs in the United States. © 2006 by the Infectious Diseases Society of America. All rights reserved.