Initial observational and retrospective studies have suggested both chloroquine and artemisinin combination therapy (ACT) are effective therapy for uncomplicated P. knowlesi infection [15, 16, 22, 23]. Justification for treatment selection for this trial is based on this literature review. Case reports predominantly from returned travelers to South-East Asia also document uncomplicated knowlesi malaria responding well to conventional anti-malarials such as chloroquine, mefloquine, atovaquone with proguanil, doxycycline and quinine [4, 24- 31], supporting its zoonotic and drug naïve origin. However to date there have been no prospective randomised trials to compare chloroquine and ACT as the anti-malarials currently used for uncomplicated P. knowlesi infection in Malaysia, and there are no current recommendations on how to treat P. knowlesi infection in the WHO 2010 malaria treatment guidelines. As ACTs are already being used for treating P. falciparum and are recommended for the increasingly chloroquine-resistant P. vivax found in the surrounding countries in South East Asia [32], the potential benefit of a unified treatment policy to facilitate prompt and effective treatment of all Plasmodium species needs evidence of ACT as the optimal treatment for P. knowlesi infection also.