In vitro studies have shown that inhibition of Plasmodium falciparum blood-stage parasite growth by antibody-dependent cellular inhibition is mediated by cooperation between malaria-specific IgG1 and IgG3, but not IgG2, and monocytes via the Fcγ receptor II (FcγRII). A single amino acid substitution at position 131 in FcγRIIa is critical in the binding of human IgG subclasses. The hypothesis that the FcγRIIa-Arg/Arg131 genotype, which does not bind to IgG2, is a host genetic factor for protection against high-density P. falciparum infection was tested. One hundred eighty-two infants from a large community-based birth cohort study in western Kenya were selected for an unmatched case-control study. Results showed that the infants with the FcγRIIa-Arg/Arg131 genotype were significantly less likely to be at risk for high-density falciparum infection, compared with infants with the FcγRIIa-His/Arg131 genotype (adjusted odds ratio, 0.278; 95% confidence interval, 0.123–0.627; P=.0021). This finding supports the hypothesis