Pyronaridine is a new antimalarial agent developed in China. In this randomized, unblinded study, the safety, tolerance, and clinical efficacy of pyronaridine (n =44) were evaluated and compared with those of chloroquine (n =44), the standard first-line antimalarial drug in most of Africa, in 88 Cameroonian children with acute uncomplicated falciparum malaria. The target sample size was determined to detect a 35% difference in in vivo resistance between the two treatment groups, with 95% power. Clinical and parasitological responses were monitored for 14 days on an outpatient basis. Seven children (3 treated with pyronaridine and 4 treated with chloroquine) were lost to follow-up and were excluded from the analysis. All 41 patients treated with pyronaridine were cured. Treatment failure was observed in 16 (40%) of the 40 children treated with chloroquine. In vitro assays indicated that 23 of 40 clinical isolates obtained from patients treated with pyronaridine were resistant in vitro to chloroquine. Side effects associated with pyronaridine intake were minor and transient. Pyronaridine is safe and well tolerated by symptomatic Cameroonian children, and it is highly efficacious in Africa, where chloroquine resistance is well established.