Five drug regimens for the treatment of acute toxoplasmosis were compared in a monkey model. Systemic disease that is almost always fatal in squirrel monkeys within 7–9 days was produced by oral inoculation of a brain suspension made from mice chronically infected with the Beverly strain of Toxoplasma gondii. All untreated controls died of toxoplasmosis (6/6) while treatment gave the following results: sulfamethoxazole, 0/3; spiramycin, 5/5; clindamycin/sulfadiazine (CLD/SLD), 0/4; primethamine/sulfadiazine (PYR/SLD), 0/5; trimethoprim/sulfamethoxazole (TMP/SMZ), 0/4. Three of the five monkeys treated with CLD/SLD died during or shortly after the experiment from probable CLD toxicity. Sulfonamides alone or in combination with PYR or TMP were significantly more effective than spiramycin in treating toxoplasmosis in this model. The dose regimen used in this study did not allow us to determine if the addition of PYR or TMP changed the protection of sulfa alone.