Delayed-type hypersensitivity (DTH) testing was evaluated as a predictor of human immunodeficiency virus (HIV) disease progression in 336 symptomatic patients with baseline CD4 cell counts of 200-500/mm3 who were participating in a randomized trial of early versus late therapy with zidovudine. Patients with a response of > 2 mm to any of seven antigens were categorized as reactive; those without were anergic. Anergic patients were significantly more likely than reactive patients to have HIV disease progression as evidenced by decrease in CD4 cell count (52% vs. 27%), development of AIDS (33% vs. 17%), or death (18% vs. 9%) (P < or = .02), irrespective of time of zidovudine initiation. By multivariate analysis, DTH results were an independent predictor of HIV progression separate from CD4 cell count, p24 antigen positivity, or level of beta 2-microglobulin. DTH skin tests are an independent predictor of HIV disease progression and may be of value in the evaluation of a patient's immune status.