Aims: To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. Methods: OZ439 was administered as single oral daily doses of a capsule formulation (50-1200mg) or an oral dispersion (400-1600mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800mg day-1). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. Results: The pharmacokinetic (PK) profile of OZ439 was characterized by a tmax of around 3h, followed by a multiphasic profile with a terminal half-life of 25-30h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t1/2 of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites. Conclusion: The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.