Fulani and Masaleit, two sympatric ethnic groups in eastern Sudan, are characterized by marked differences in susceptibility to Plasmodium falciparum malaria. It has been suggested that sickle cell trait carriage may protect from the most severe forms of malaria. Previously, we have shown that FcgammaRIIa polymorphism is associated with the outcome of malaria disease. The present study aimed at determining whether the two tribes differ in the frequency of FcgammaRIIa and Hb AS genotypes. For this, genotyping of FcgammaRIIa and Hb AS in 70 Fulani and 70 Masaleit age- and sex-matched subjects was conducted. The frequency of FcgammaRIIa H/H131 genotype was higher in the Fulani as compared to the Masaleit group (40.0% versus 14.3%; adjusted odd ratio [OR]=3.05, 95% confidence interval [CI]=1.19-7.82 and P=0.02), while the R/R131 genotype was significantly higher in the Masaleit group (14.3% for Fulani versus 45.0% for Masaleit; adjusted OR=0.26, 95% CI=0.11-0.64 and P<0.01). With regard to FcgammaRIIa allele frequencies, there were significant differences between the Fulani and Masaleit ethnic groups. Thus, the H131 allele was more frequent than the R131 among Fulani children (0.63 versus 0.37, OR=3.23, 95% CI=1.93-5.45 and P<0.001). The frequency of the Hb AS genotype was lower in the Fulani compared to the Masaleit group (15.7% versus 30.0%, respectively, adjusted OR=0.02, CI=0.01-0.18 and P<0.01). These data suggest that FcgammaRIIa and Hb AS polymorphisms may contribute to the clinical outcome of malaria. We conclude that the H/H131 genotype and H131 allele rather than Hb AS genotype (sickle cell trait patients) appear to associate with the Fulani ethnic group.