A critical step in infection by Plasmodium falciparum, the microorganism that causes the most severe form of malaria, is the adhesion of parasitized red blood cells to capillary endothelium. The human protein CD36 is a major receptor for P. falciparum-infected red blood cells^, and may contribute to the disease by sequestering infected red blood cells^, and inhibiting the immune response to the parasite. We have found that African populations contain an exceptionally high frequency of mutations in CD36. Unexpectedly, these mutations that cause CD36 deficiency are associated with susceptibility to severe malaria, suggesting that the presence of distinct CD36 mutations in Africans and Asians^,, is due to some selection pressure other than malaria.