Clarithromycin, a new macrolide, is effective in treating experimental Toxoplasma gondii infection. A pyrimethamine-clarithromycin combination was evaluated for the treatment of acute Toxoplasma encephalitis in 13 AIDS patients. The scheduled regimen was 2 g of clarithromycin per day and 75 mg of pyrimethamine per day for 6 weeks. The protocol was completed in eight patients and stopped in five patients (because of voluntary withdrawal by two patients, deterioration of neurological condition and thrombocytopenia in two patients, and suspicion of liver toxicity in one patient). The clinical and computed tomography scan responses at week 6 of treatment were 80 and 50%, respectively. Two patients died, one of toxoplasmic encephalitis and the other of cerebral bleeding due to pyrimethamine-induced thrombocytopenia. Adverse events related to therapy were nausea and/or vomiting (38%), skin rash (38%), significant increase of liver tests (24%), hearing loss (15%), and severe hematological abnormalities (31%). In this pilot study, a pyrimethamine-clarithromycin combination was shown to be comparable to the conventional regimen for the treatment of acute Toxoplasma encephalitis in AIDS patients.