Background. Drug-resistant Plasmodium falciparum malaria necessitates development of novel drugs for treatment. The present study assessed the efficacy and safety of 3 dose levels of arterolane (RBx 11160), a synthetic trioxolane, for treatment of acute uncomplicated falciparum malaria.Methods. In this randomized, double-blind, multicenter, parallel-group, dose-finding, phase II trial, 230 patients from 4 centers in Thailand, India, and Tanzania (mainland and Zanzibar) received either 50 mg (n = 78), 100 mg (n = 76), or 200 mg (n = 76) of arterolane once daily for 7 days. Patients (aged 13–65 years) with asexual parasite density of 1000–100,000 parasites/mL were included and were followed up for 28 days. The median time to 90% parasite clearance (PC90) was evaluated.Results. The median PC90 was longer in the group receiving the 50-mg dose (19.4 h), compared with the groups receiving the 100-mg dose (12.8 h) and 200-mg dose (12.6 h) (P <.01). The polymerase chain reaction–corrected adequate clinical and parasitological responses on day 28 were 63%, 71%, and 72% for the groups receiving the 50-mg, 100-mg, and 200-mg doses, respectively, by intention-to-treat analysis (odds ratio, 1.55; 95% confidence interval, 0.78–3.06, for comparison of the 200-mg and 50-mg dose groups). Treatment was generally well tolerated. No patient died or experienced any serious adverse event. Mild complaints were reported in < 10% of the patients and were similar in the 3 groups. Biochemistry and hematological analyses did not show any sign of drug toxicity in any patient.Conclusion. Arterolane at daily doses of 100 and 200 mg is a rapidly acting, effective, and safe synthetic antimalarial drug, which may potentially represent an alternative to artemisinin derivatives in antimalarial combination therapy