Using data from a large cohort of Ugandan adults and children followed longitudinally with careful prospective surveillance for both P. falciparum parasitemia and clinical malaria, we identified two class I HLA alleles, HLA-C*06:02 and HLA-B*53:01, that were associated with an increased prevalence of P. falciparum parasitemia. The gene discussed is HLA-B; the disease is malaria.