Controlled human malaria infection (CHMI) using cryopreserved non-attenuated Plasmodium falciparum sporozoites (PfSPZ) offers a unique opportunity to investigate naturally acquired immunity (NAI). By analyzing blood samples from 5 malaria-na?ve European and 20 African adults with lifelong exposure to malaria, before, 5, and 11?days after direct venous inoculation (DVI) with Sanaria PfSPZ Challenge, we assessed the immunological patterns associated with control of microscopic and submicroscopic parasitemia. All (5/5) European individuals developed parasitemia as defined by thick blood smear (TBS), but 40% (8/20) of the African individuals controlled their parasitemia, and therefore remained thick blood smear-negative (TBS Africans). In the TBS Africans, we observed higher baseline frequencies of CD4 T cells producing interferon-gamma (IFNγ) that significantly decreased 5?days after PfSPZ DVI. The TBS Africans, which represent individuals with either very strong and rapid blood-stage immunity or with immunity to liver stages, were stratified into subjects with sub-microscopic parasitemia (TBSPCR) or those with possibly sterilizing immunity (TBSPCR). Higher frequencies of IFNγTNFCD8 γδ T cells at baseline, which later decreased within five days after PfSPZ DVI, were associated with those who remained TBSPCR. These findings suggest that naturally acquired immunity is characterized by different cell types that show varying strengths of malaria parasite control. While the high frequencies of antigen responsive IFNγCD4 T cells in peripheral blood keep the blood-stage parasites to a sub-microscopic level, it is the IFNγTNFCD8 γδ T cells that are associated with either immunity to the liver-stage, or rapid elimination of blood-stage parasites.