Immunoglobulin G (IgG) cross-linking with Fc gamma receptor IIIB (FcγRIIIB) triggers neutrophil degranulation, releasing reactive oxygen species with high levels associated with protection against malaria. The FCGR3B-c.233C>A polymorphism thought to influence the interaction between IgG and FcγRIIIB was recently associated with malaria. We studied the statistical interaction between glutamate rich protein antibodies and FCGR3B-c.233C>A genotypes on risk of malaria in a cohort of Ghanaian children. The absolute risk of malaria decreased more rapidly with increasing antibody levels for 233AA/AC individuals compared with 233CC children. This genotype related effect modification may significantly influence malaria sero-epidemiological and vaccine trial studies.