Background: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated P.falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (25 kg), at recommended dose regimens. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) years of age. An evidence-based optimised dose regimen was constructed which provided equivalent piperaquine exposures across all ages without exceeding the concentration range observed with the manufacturers recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. Conclusion: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in young children with malaria. This should prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization Technical Guidelines Development group in the development of the recently published treatment guidelines (2015).