OBJECTIVE To evaluate whether pediatric patients infected with human immunodeficiency virus (HIV) can mount appropriate delayed-type hypersensitivity (DTH) skin responses to recall antigens and whether these responses can be correlated with clinical or immunologic parameters. METHODS Prospective evaluation of DTH responses in HIV-infected children. Uninfected children born to HIV-infected mothers served as control subjects. Antigens used for yearly DTH testing included Candida albicans (1:100, 1:10); mumps virus; Trichophyton; purified protein derivative of tuberculin; and tetanus toxoid (1:100, 1:10). At the time of each DTH test, patients were staged according to two Centers for Disease Control and Prevention pediatric HIV classification systems, and T-cell subsets were obtained. RESULTS Twenty-seven HIV-infected patients with a median age at entry of 74.1 (range, 12 to 156) months were followed. Forty-four DTH skin tests in 21 symptom-free HIV-infected patients (PI) and 18 tests in 10 HIV-infected patients with symptoms (P2), as well as 43 DTH skin tests in 18 patients who had either mild or moderate clinical symptoms or immunosuppression and 19 tests in 13 patients with severe symptoms or immunosuppression, were evaluated. Sixteen DTH skin tests were performed in 14 uninfected patients. HIV-infected patients tended to have fewer DTH responses to antigens and of smaller size than did uninfected patients. When controlled for age, few differences in DTH responsiveness were seen between HIV-infected and uninfected patients. Anergy was associated with symptomatic disease, evidence of advanced clinical or immunologic disease, and low CD4+ percentages (p <0.05). CONCLUSIONS HIV-infected children are able to mount antigen-specific cell-mediated immune responses that are qualitatively similar to those of age-matched control subjects. Loss of DTH responsiveness correlates with both clinical and immunologic evidence of HIV disease progression.