BACKGROUND: In previous studies, delayed-type hypersensitivity (DTH) skin testing has been shown to be affected by several factors including nutritional status, intercurrent infection, host immune status, and previous exposure to the antigen being used. OBJECTIVE: To determine the effect of human immunodeficiency virus type 1 (HIV-1) status on DTH skin testing in a cohort of HIV-1-infected and noninfected Ugandan children followed prospectively from birth. DESIGN: Nested case-control study. SETTING: Primary care clinic serving study participants at Mulago Hospital, Makerere University, Kampala, Uganda. PARTICIPANTS: Thirty HIV-1-infected children and 30 age-matched, HIV-1-noninfected children. METHODS: After completion of history and physical, each child underwent Mantoux skin testing with both Candida and purified protein derivative (PPD). Results of skin testing were read in 48 to 72 hours. Complete chart reviews were performed on all children. CD4 lymphocyte counts were obtained on all HIV-1-infected children at the time the skin testing was read. RESULTS: The average age of participants was 67 months (range, 51-92 months). HIV-1-infected children (mean CD4 lymphocyte count, 1069 mL-1; range, 86-3378 mL-1), compared with noninfected, age-matched peers, developed significantly smaller PPD reaction size (mean, 1.18 mm +/- 4.3 vs 3.6 mm +/- 7.6, respectively). Candida responses were not different between the two groups of children. Among HIV-1-infected children, there was a larger Candida reaction size in children who had recently received chloroquine treatment. There was no significant correlation between Candida reactivity and PPD reactivity, progressive HIV-1 disease, or CD4 lymphocyte count. The six children diagnosed clinically with active tuberculosis had lower absolute CD4 lymphocyte counts than children without tuberculosis. Lack of reaction to PPD was associated with lower CD4 lymphocyte counts and progressive HIV-1 disease. CONCLUSIONS: In HIV-1-infected Ugandan children, DTH skin testing was influenced by the choice of antigen selected, HIV-1 infection, and recent treatment with chloroquine. Based on these findings, we believe that further prospective, longitudinal investigation into the role of chloroquine in HIV-1-infected children is needed. We emphasize the limitations of DTH skin testing in HIV-infected children as an adjunct in the diagnosis of active tuberculosis.