BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) is important in the control 
of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. 
Mutations in this enzyme produce X-linked deficiency states associated with 
protection against malaria, notably in Africa where the A- form of G6PD 
deficiency is widespread. Some reports have proposed that heterozygous females 
with mosaic populations of normal and deficient erythrocytes (due to random X 
chromosome inactivation) have malaria resistance similar to or greater than 
hemizygous males with populations of uniformly deficient erythrocytes. These 
proposals are paradoxical, and they are not consistent with currently 
hypothesized mechanisms of protection.
METHODS AND FINDINGS: We conducted large case-control studies of the A- form of 
G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic 
populations of rural Mali, West Africa, where malaria is hyperendemic. Our 
results indicate that the uniform state of G6PD deficiency in hemizygous male 
children conferred significant protection against severe, life-threatening 
malaria, and that it may have likewise protected homozygous female children. No 
such protection was evident from the mosaic state of G6PD deficiency in 
heterozygous females. We also found no significant differences in the parasite 
densities of males and females with differences in G6PD status. Pooled odds 
ratios from meta-analysis of our data and data from a previous study confirmed 
highly significant protection against severe malaria in hemizygous males but not 
in heterozygous females. Among the different forms of severe malaria, protection 
was principally evident against cerebral malaria, the most frequent form of 
life-threatening malaria in these studies.
CONCLUSIONS: The A- form of G6PD deficiency in Africa is under strong natural 
selection from the preferential protection it provides to hemizygous males 
against life-threatening malaria. Little or no such protection is present among 
heterozygous females. Although these conclusions are consistent with data from 
at least one previous study, they have not heretofore been realized to our 
knowledge, and they therefore give fresh perspectives on malaria protection by 
G6PD deficiency as an X-linked trait.