We conducted a prospective multicenter study of the efficacy of current therapeutic strategies for ocular toxoplasmosis in 149 patients. Treatment consisted of the following three triple-drug combinations: group 1, pyrimethamine, sulfadiazine, and corticosteroids; group 2, clindamycin, sulfadiazine, and corticosteroids; and group 3, trimethoprim, sulfamethoxazole and corticosteroids. Patients with peripheral retinal lesions were not treated systemically. No difference in the duration of inflammatory activity was observed between treated and untreated patients (P = .5). The most important factor predicting the duration of inflammatory activity was the size of the retinal lesion itself, independent of the treatment (P < .001). We found a reduction in size of the retinal inflammatory lesion for 49% of the pyrimethamine-treated patients (17 of 35) compared to 20% of the untreated patients (eight of 41) (P < .01). However, the most frequent occurrence of side effects was also associated with pyrimethamine medication (26%, nine of 35). The mean recurrence rate after three years of follow-up was 49% for all patients (60 of 122 patients), with no differences between treated and untreated patients (P = .6).