AbstractObjectivesCutaneous leishmaniasis (CL) is a neglected tropical disease causing a range of skin lesions for which safe and efficacious drugs are lacking. Oleylphosphocholine (OLPC) is structurally similar to miltefosine and has previously demonstrated potent activity against visceral leishmaniasis. We here present thein vitroandin vivoefficacy of OLPC against CL-causingLeishmaniaspecies.MethodsThe antileishmanial activities of OLPC were evaluated and compared with miltefosinein vitroagainst intracellular amastigotes of seven CL-causing species. Following the confirmation of significantin vitroactivity, the performance of the maximum tolerated dose of OLPC was evaluated in an experimental murine model of CL followed by a dose–response titration and the efficacy evaluation of four OLPC formulations (two with a fast-release and two with a slow-release profile) using bioluminescentLeishmania majorparasites.ResultsOLPC demonstrated potentin vitroactivity of the same order as miltefosine in the intracellular macrophage model against a range of CL-causing species. A dose of 35 mg of OLPC/kg/day administered orally for 10 days was well-tolerated and able to reduce the parasite load in the skin ofL. major-infected mice to a similar extent as the positive control paromomycin (50 mg/kg/day, intraperitoneally) in bothin vivostudies. Reducing the dose of OLPC resulted in inactivity and modifying the release profile using mesoporous silica nanoparticles led to a decrease in activity when solvent-based loading was used in contrast to extrusion-based loading, which had no impact on its antileishmanial efficacy.ConclusionsTogether, these data suggest that OLPC could be a promising alternative to miltefosine treatment for CL. Further investigations exploring experimental models with additionalLeishmaniaspecies and skin pharmacokinetic and dynamic analyses are required.