OBJECTIVE: To report the results of a phase I trial to evaluate the safety and efficacy of atovaquone for the treatment of ocular toxoplasmosis in immunocompetent patients. DESIGN: Open label, nonrandomized, prospective, clinical trial. PARTICIPANTS: Seventeen immunocompetent patients between the ages of 18 and 75 years with clinical and serologic evidence of ocular toxoplasmosis participated. INTERVENTION: Treatment of ocular toxoplasmosis with atovaquone tablets (750 mg four times a day) for 3 months. Prednisone (40 mg) tablets were added on day 3 of treatment and tapered as inflammation resolved. MAIN OUTCOME MEASURES: Clinical response and patient tolerance to atovaquone therapy for ocular toxoplasmosis. RESULTS: Average follow-up was 10 months. Most patients experienced no adverse treatment effects. When present, side effects were usually mild and included rash, pruritus, headache, and nausea. With the exception of one patient, who discontinued treatment at 6 weeks secondary to persistent epigastric discomfort, all patients completed the 12 weeks of therapy. All patients had a favorable response to treatment that began within 1 to 3 weeks. Visual acuity was stabilized or improved in all patients. Median initial visual acuity was 20/200 and median final visual acuity was 20/25. In general, atovaquone was well tolerated. CONCLUSIONS: Atovaquone is better tolerated than conventional antitoxoplasmosis therapy and appears to be at least as effective. Atovaquone is a promising alternative for the treatment of ocular toxoplasmosis in immunocompetent patients.