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A triple-blind, randomized, clinical trial was undertaken in a Brazilian Amazon region to compare the effectiveness of oral artesunate (seven days, total dose = 0.75 g) plus tetracycline (seven days, total dose = 10.5 g) (AT) and oral quinine (three days, total dose = 6 g) plus tetracycline (seven days, total dose = 10.5 g) (QT) against uncomplicated Plasmodium falciparum malaria. Effectiveness was assessed by cure rates (World Health Organization [WHO]) and parasite clearance at day 2. Patients were randomized, 88 to each group. The groups had similar baseline clinical characteristics. The incidence of side effects was much higher in the QT group (82%) than in the AT group (50%) (P < 0.001). Cure rates were similar: 80% in the AT group and 77% in the QT group (P = 0.68). Parasitemia (by day 2) cleared faster in the AT group than in the QT group (98.5% versus 47.6%, respectively; P < 0.001). These results indicate that the combination of artesunate plus tetracycline is effective in the treatment of uncomplicated falciparum malaria and may provide a useful alternative to other treatment regimens.