The high prevalence of hemoglobin S (HbS) in Africa and hemoglobin C (HbC) in parts of West Africa is caused by the strong protection against severe falciparum malaria during childhood. Much less is known about the effect of HbS and especially HbC on Plasmodium falciparum infection, uncomplicated malaria, and anemia. A total of 1070 children from the Ashanti Region, Ghana, were enrolled at the age of 3 months and visited monthly until 2 years of age. The effects of the beta-globin genotype on the age-dependent incidence of malaria, levels of parasitemia, and hemoglobin as well as physical development were analyzed by population-averaged models. Infants with HbAS were protected from uncomplicated malaria (P < .005) and anemia (P < .001), had lower age-adjusted parasite densities (P < .001), and higher age-adjusted hemoglobin levels compared with children with the HbAA genotype (P = .004). In contrast, HbAC carriers had lower hemoglobin levels (P < .033) and were not protected against malaria or anemia. Notably, infants with HbAS were also significantly protected against stunting compared with carriers of HbAA or HbAC. This indicates differing mechanisms of protection against malaria of HbAS and HbAC and might help to understand why HbC is restricted to distinct areas of West Africa.