Cotrimoxazole (trimethoprim/sulfamethoxazole [TMP-SMX]) is an alternative treatment for toxoplasmic encephalitis because it is inexpensive, well-tolerated, and as effective as pyrimethamine-sulfadiazine, which is the first-line drug regimen). We report results of a large cohort study of patients with acquired immunodeficiency syndrome who were treated for toxoplasmic encephalitis with cotrimoxazole. The mean follow-up period was more than three years. Our results confirm that cotrimoxazole is effective (85.5%), with a relatively low incidence of side effects (22%; 7.4% requiring treatment interruption). Relapse occurred in 30.1% of the patients at a mean +/- SD of 7.8 +/- 16.2 months after the first episode. The only risk factor for relapse was poor treatment and/or prophylaxis adherence. Mortality was significantly higher (P < 0.05) before 1996 than after 1996 (the era of highly active antiretroviral therapy). There was a non-significant trend towards a higher rate of relapse among patients treated before 1996 (P = 0.06). Consequently, cotrimoxazole could be a first-line drug regimen for curative treatment and prophylaxis of toxoplasmic encephalitis.