Background: Malaria has been and is still a major protozoan disease affecting the human population. Erythrocyte polymorphisms (mainly in blood groups and genotypes) influence the susceptibility to severe malaria. Aim: This study is aimed at assessing the prevalence of malaria in relation to human blood factor and to identify the susceptibility of malaria to these factors. Methods: The prevalence of malaria with blood groups and genotypes were determined in 206 subjects attending the three major medical centres in Eku-Abraka metropolis. Results: It was found that blood group O was present in 60.68% of the population, with 17.98%, 16.99% and 4.37% in B, A and AB respectively, while genotype AA was highest with 75.73% prevalence. Blood group O+ was associated with 85.71% infection, as the... most susceptible of the blood groups. It was shown that dominant homozygotes, HbAA, were more susceptible than the sickle cell trait, HbAS, while sickle cell disease, HbSS, were most vulnerable to the plasmodial parasite. A combination of blood group O+ and AS genotype showed the least susceptibility to malaria with significant sample size. Conclusion: This work provides insights into the relationship between malaria, blood groups and genotypes.