Isosporiasis is an uncommon but important diarrheal disease of humans that, like cryptosporidiosis, is life-threatening in patients with the acquired immunodeficiency syndrome (AIDS). Isospora belli infection responds rapidly to therapy with trimethoprim-sulfamethoxazole, but patients with AIDS have a high rate of adverse reactions to this therapy. The cases of two patients with AIDS, sulfonamide allergy, and I. belli infection are reported. They were treated successfully with pyrimethamine alone, 75 mg/d, and recurrence was prevented with daily pyrimethamine therapy, 25 mg/d. In patients with AIDS with sulfonamide allergy or intolerance, pyrimethamine alone seems to be a reasonable alternative therapy for I. belli infection.