Background. Although suppositories of artemisinin derivatives may be a valuable option for treatment of malaria in children when circumstances prevent oral and parenteral therapy, few confirmatory data have been published. Methods. We assessed the safety and efficacy of rectal artesunate in 47 children ages 5 to 10 years with uncomplicated malaria acquired in a hyperendemic area of Papua New Guinea. Thirty were symptomatic and had Plasmodium falciparum parasitemia > 2000/mul (Group 1), 12 had P. falciparum and either a parasitemia < 2000/mul or minimal/no symptoms (Group 2) and 5 had Plasmodium vivax (Group 3). Each child received rectal artesunate 10 to 15 mg/kg at 0 and 12 h. After monitoring for 24 h, chloroquine plus sulfadoxine/pyrimethamine was given, and the patient discharged. Results. Artesunate suppositories were well-tolerated. After 24 h only one child (from Group 1) had persistent parasitemia, and only one (from Group 3) had not defervesced. These two children received intramuscular quinine and recovered uneventfully. Three Group 2 children redeveloped fever and tachycardia at 24 h, but each responded to simple supportive measures and remained aparasitemic. Conclusions. Intrarectal artesunate is safe, effective initial treatment for uncomplicated malaria in children. A transient fever spike can sometimes occur after parasite clearance. We recommend that children with uncomplicated malaria receive two doses of 2:10 mg/kg rectal artesunate within the first 24 h.