To evaluate combined prophylaxis for Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis, 533 patients with symptomatic human immunodeficiency virus infection and/or CD4 lymphocyte counts of < 200/microL were randomized to receive dapsone/pyrimethamine (200/75 mg once weekly) or aerosolized pentamidine (300 mg every 4 weeks). The median CD4 lymphocyte count was 110/microL; 47.5% were seropositive for toxoplasma antibodies. The median duration of follow-up was 483 days. In the intent-to-treat analysis, 12 cases of PCP and 14 of toxoplasmic encephalitis occurred in the dapsone/pyrimethamine group and 13 and 20 cases, respectively, in the aerosolized pentamidine group (adjusted relative risk for toxoplasmosis, 0.56; P =.10). However, only two of the 14 cases of toxoplasmic encephalitis in the dapsone/pyrimethamine group developed during actual treatment. The mortality among the two groups was similar. Dapsone/pyrimethamine was not tolerated by 30% of participants. A subanalysis of 240 matched, tolerant patients yielded a relative risk for toxoplasmosis of 0.21 (P =.014), a result favoring the use of dapsone/pyrimethamine. Dapsone/pyrimethamine was as effective as aerosolized pentamidine as prophylaxis for PCP and significantly reduced the incidence of toxoplasmic encephalitis among those participants who tolerated it.