Malaria has been a major selective force on the human population, and several 
erythrocyte polymorphisms have evolved that confer resistance to severe malaria. 
Plasmodium falciparum rosetting, a parasite virulence phenotype associated with 
severe malaria, is reduced in blood group O erythrocytes compared with groups A, 
B, and AB, but the contribution of the ABO blood group system to protection 
against severe malaria has received little attention. We hypothesized that blood 
group O may confer resistance to severe falciparum malaria through the mechanism 
of reduced rosetting. In a matched case-control study of 567 Malian children, we 
found that group O was present in only 21% of severe malaria cases compared with 
44-45% of uncomplicated malaria controls and healthy controls. Group O was 
associated with a 66% reduction in the odds of developing severe malaria 
compared with the non-O blood groups (odds ratio 0.34, 95% confidence interval 
0.19-0.61, P < 0.0005, severe cases versus uncomplicated malaria controls). In 
the same sample set, P. falciparum rosetting was reduced in parasite isolates 
from group O children compared with isolates from the non-O blood groups (P = 
0.003, Kruskal-Wallis test). Statistical analysis indicated a significant 
interaction between host ABO blood group and parasite rosette frequency that 
supports the hypothesis that the protective effect of group O operates through 
the mechanism of reduced P. falciparum rosetting. This work provides insights 
into malaria pathogenesis and suggests that the selective pressure imposed by 
malaria may contribute to the variable global distribution of ABO blood groups 
in the human population.