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BACKGROUND: Experimental inoculation of viableP. falciparumsporozoites administered with blood-stage chemoprevention results in protective immunity. It is unclear if chemoprevention similarly enhances immunity following natural exposure to malaria. METHODS: We assessedPf-specific T cell responses among Ugandan children who were randomized to receive monthly dihydroartemisinin-piperaquine (DP, n=87) or no chemoprevention (n=90) from 6 to 24 months of age, with pharmacologic assessments for adherence, then clinically followed for an additional year. RESULTS: During the intervention, monthly DP reduced malaria episodes by 55% (P<0.001), and by 97% among children who were highly adherent to DP (P<0.001). In the year after the cessation of chemoprevention, children who were highly adherent to DP had a 55% reduction in malaria incidence compared to children given no chemoprevention (P=0.004). Children randomized to DP had higher frequencies of iRBC-specific CD4+T cells co-producing IL-2/TNFalpha (P=0.003), which were associated with protection from subsequent clinical malaria and parasitemia, and fewer CD4+T cells co-producing IL-10/IFNgamma (P=0.001), which were associated with increased risk. CONCLUSION: In this setting, effective antimalarial chemoprevention fostered the development of TNF/IL2-producing CD4+T cells that were associated with prospective protection, while limiting CD4 production of immunoregulatory IL10.