To determine the spectrum of pathogens causing acute febrile respiratory illness in human immunodeficiency virus (HIV)-infected adults, we re-analyzed data from a prospective surveillance study involving 50 outpatients (90% of whom received highly active antiretroviral therapy). Nasopharyngeal samples were tested for 23 respiratory viruses by multiplex reverse-transcriptase polymerase chain reaction (PCR) and for atypical bacteria by PCR. Sputum cultures and serological testing were performed. Viruses accounted for 64% of infections. After influenza (22 cases), human metapneumovirus infection (6 cases) was most common and was associated with bronchospasm. Bacterial infections occurred in 6 patients (3 of whom had concurrent viral infection). Over 80% of patients received antibiotics. Rapid testing to identify specific viral pathogens could aid in patient management and reduce unnecessary antibiotic exposure.