Background:Mass drug administration (MDA) may further reduce malaria transmission in low transmission areas. The impact of MDA on dynamics of malaria transmission was determined in a prospective cohort study. Methods:Annual rounds of MDA with dihydroartemisinin-piperaquine (DP) were implemented over two years (2014 and 2015) in six village pairs before the malaria transmission season. Monthly blood samples were collected from all residents between July and December for microscopy and nested PCR. The incidence and prevalence of infection and clinical disease, and the risk of malaria re-infection post-MDA were determined. Results:Coverage of three DP doses was 68.2% (2014) and 65.6% (2015), compliance was greater than 80%. Incidence of infection was significantly lower in 2014 (IR=0.2 PPY) than in 2013 (IR=1.1 PPY) (P<0.01); monthly infection prevalence declined in the first three months post-MDA. Clinical malaria incidence was significantly lower in 2014 (IR=0.1 PPY) and 2015 (IR=0.2 PPY) than in 2013 (IR=0.4 PPY) (P<0.01) but remained higher in eastern Gambia. Individuals infected before MDA had a 2-fold higher odds of re-infection post-MDA (AOR=2.5, 95% CI: 1.5-4.3, P<0.01). Conclusions:MDA reduced malaria infection and clinical disease during the first months of each transmission season. The reduction was maintained in low transmission areas, but not in eastern Gambia. One MDA round could be followed by focal MDA targeting individuals found infected during the dry season. Repeated MDA rounds, some of them during the dry season over a much larger geographical area, may result in a more marked and sustained decrease of malaria transmission.