Atovaquone is a new hydroxy-napthoquinone antiprotozoal agent active againstPneumocystis cariniiin vitro and in animal models. The authors report an experience using atovaquone to treat 25 patients with mild to moderateP. cariniipneumonia. Eligible patients were treated for 21 days with 750 mg of atovaquone orally three times daily. Prednisone was added when the P(A-a)O2gradient was between 35–45 mm Hg. Patients were treated under three treatment protocols. Patients in Group 1 participated in one of two randomized comparative drug trials, designed for patients with and without sulfonamide intolerance. Six of seven patients successfully completed treatment, and one patient discontinued treatment because of an adverse reaction (>5 times baseline increase in transaminase level). Patients in Group 2 were treated with atovaquone for mild to moderateP. cariniipneumonia under a treatment Investigational New Drug protocol because of prior sulfonamide reactions. Fifteen of these 18 patients successfully completed treatment; one died from other complications during treatment and two discontinued treatment for adverse reactions (>5 times baseline increase in transaminase levels, and a diffuse rash). Serum transaminase levels returned to normal at the end of treatment in all patients with elevated levels. All patients demonstrated clinical resolution of their pneumonia and improvement of pretreatment hypoxemia (Group 1: pretreatment PaO2= 82 ± 14 mm Hg, posttreatment PaO2= 92 ± 9 mm Hg). Overall, 21 (84%) of 25 patients successfully finished therapy without significant adverse reactions. Atovaquone appears to be an effective and well-tolerated oral treatment for mild to moderateP. cariniipneumonia. The main toxicities appear to be a reversible serum transaminase rise and a nondesquamating rash. Currently, atovaquone should be considered as an alternative therapy for intolerant patients or as salvage therapy.