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Background: To restrict trial endpoints to infections acquired after vaccination in Phase IIb trials of candidate malaria vaccines, participants are treated with anti-malarial drugs to clear existing infections. Anti-malarial drugs with a long half-life may inhibit the acquisition of new infections. This study evaluated the effects of three anti-malarial drug regimens on the clearance of existing infections and acquisition of new infections. Methods: An open-label randomised controlled trial (MalPaC) was conducted between November 2013 and February 2014. Ninety adults were randomised 1:1:1 to receive one of three treatments: atovaquone/proguanil and artesunate (AP+AS); artesunate (AS); or sulphadoxine-pyrimethamine, artesunate, and primaquine (SP+AS+PQ). Parasite monitoring was determined over 84-day follow-up by assessing Plasmodium falciparum positivity by 18s qPCR, live and sexual stage parasites by RT-PCR, and recrudescence of infections by msp2 genotyping. Results: At enrolment, parasite prevalence by qPCR was 44% (40/90, day 0), which fell to 10% (9/90, day 16), then rose to almost the initial rates by day 84 (39%, 35/90). Individuals treated with AS and SP+AS+PQ were more likely to have higher qPCR positive rates compared to participants treated with AP+AS in the immediate post-treatment phase (days 16-28) (OR=7.7 [95%CI 4.6-12.8] p Conclusion: Falciparum DNA remained detectable by PCR post-treatment with incomplete parasite clearance regardless of drug regimen. Though AP+AS drug regimen may also have partially suppressed the acquisition of new infections during post-treatment follow-up. Trial registration: Pan African Clinical Trials Registry, 22nd of August 2013, PACTR201309000625311.