Thalidomide is emerging as a useful agent in the management of several complications of disease due to human immunodeficiency virus (HIV). We conducted three prospective studies of 56 HIV-infected patients who were treated with thalidomide for 14-21 days; 24 (43%) of these patients discontinued therapy owing to adverse reactions. Cutaneous and/or febrile reactions were the most frequent toxicities, arising in 20 (36%) of the patients. These reactions occurred after a mean interval (+/-SD) of 10 +/- 3 days and were associated with significantly lower CD4 T lymphocyte counts in reactors than in nonreactors (median count, 52.5/mm3 vs. 242 cells/mm3, respectively; P = .009). Four of four rechallenged patients experienced accelerated hypersensitivity; hypotension occurred in one case. Although sedation was an almost universal side effect among the patients, it was moderate or severe in only seven (13%); constipation was moderate or severe in five (9%) of the patients. Severe neuropathic symptoms and mood changes were each noted in two (4%) of the 56 patients. We conclude that the increasing use of thalidomide to treat HIV-infected patients must be accompanied by recognition of the drug's increased potential for toxicity in this population.