Pyrimethamine, 25 mg thrice weekly, was evaluated as primary prophylaxis for toxoplasmic encephalitis (TE) in a double-blind, randomized clinical trial in patients with human immunodeficiency virus (HIV) disease, absolute CD4 lymphocyte count of <200/μL (or prior AIDS-defining opportunistic infection), and the presence of serum IgG to Toxoplasma gondii. Leucovorin was coadministered only for hematologic toxicity. There was a significantly higher death rate among patients receiving pyrimethamine (relative risk [RR], 2.5; 95% confidence interval [CI], 1.3-4.8; P =.006), even after adjusting for factors predictive of survival. The TE event rate was low in both treatment groups (not significant). Only 1 of 218 patients taking trimethoprim-sulfamethoxazole but 7 of 117 taking aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia developed TE (adjusted RR for the trimethoprim-sulfamethoxazole group, 0.16; 95% CI, 0.01-1.79; P =.14). Thus, for HIV-infected patients receiving trimethoprim-sulfamethoxazole, additional prophylaxis for TE appears unnecessary.