Plasmodium falciparum, the causative agent of human malaria, invades host 
erythrocytes using several proteins on the surface of the invasive merozoite, 
which have been proposed as potential vaccine candidates. Members of the 
multi-gene PfRh family are surface antigens that have been shown to play a 
central role in directing merozoites to alternative erythrocyte receptors for 
invasion. Recently, we identified a large structural polymorphism, a 0.58Kb 
deletion, in the C-terminal region of the PfRh2b gene, present at a high 
frequency in parasite populations from Senegal. We hypothesize that this region 
is a target of humoral immunity. Here, by analyzing 371 P. falciparum isolates 
we show that this major allele is present at varying frequencies in different 
populations within Senegal, Africa, and throughout the world. For allelic 
dimorphisms in the asexual stage antigens, Msp-2 and EBA-175, we find minimal 
geographic differentiation among parasite populations from Senegal and other 
African localities, suggesting extensive gene flow among these populations 
and/or immune-mediated frequency-dependent balancing selection. In contrast, we 
observe a higher level of inter-population divergence (as measured by F(st)) for 
the PfRh2b deletion, similar to that observed for SNPs from the sexual stage 
Pfs45/48 loci, which is postulated to be under directional selection. We confirm 
that the region containing the PfRh2b polymorphism is a target of humoral immune 
responses by demonstrating antibody reactivity of endemic sera. Our analysis of 
inter-population divergence suggests that in contrast to the large allelic 
dimorphisms in EBA-175 and Msp-2, the presence or absence of the large PfRh2b 
deletion may not elicit frequency-dependent immune selection, but may be under 
positive immune selection, having important implications for the development of 
these proteins as vaccine candidates.