Malaria has exerted potent selective pressure on the human genome over millennia and has been a significant force in shaping human evolution. We have determined in 424 individuals living in malaria-hyperendemic areas in Ghana and in the Democratic Republic of Congo, the genotypes at the loci , , , and . By qPCR we have also estimated parasitemia in all these subjects. We found that 41% of individuals tested had one protective variant, 20.5% two variants, 6.4% three variants, and 0.7% four variants. We have confirmed that , , and are associated with lower parasite density. The highest allele frequency was that of , approaching 0.2, and we found that it is in linkage disequilibrium with While overall malaria prevalence did not differ significantly among the groups, non-pregnant individuals with multiple protective alleles had lower rates of high-density parasitaemia, suggesting an additive effect of these variants against severe malaria infection, while pregnancy showed different allele protection profile. The high frequency of individuals carrying two or more protective polymorphisms might have implications for malaria transmission and parasite reservoir maintenance. Thus, the significance of additive or possibly synergistic effects of multiple protective genes co-existing in the same person deserves further investigation.