Malaria is a public health problem in the KSA. It is restricted to the southwestern region, where P. falciparum is the most prevalent species. The immune response which affects the clinical outcome of malaria is genetically controlled and is influenced with high degree of HLA genetic polymorphism. The present study aimed at assessing the relationship between HLA-DRB1 alleles and malaria susceptibility pattern moreover its degree of severity in a group of Saudi population in Jazan, KSA. A total of 60 malaria cases (51 uncomplicated and 9 severe malaria cases) and 60 control subjects were enrolled in this study. Blood samples were collected and genotyping of the HLA-DRB1 alleles was performed. The results suggested significant associations of HLA-DRB1* 04 and HLA-DRB1* 11 with susceptibility to malaria (p = 0.002 and p = 0.043, respectively) and association of HLA-DRB1* 13 with resistance to malaria (p = 0.032). The HLA-DRB1* 04 was found to be associated with severe malaria. The individuals with HLA-DRB1* 04 and HLA-DRB1* 11 were at increased risk to malaria infection and the HLA-DRB1* 04 carriers are more susceptible to severe malaria. While, HLA-DRB1* 13
carriers are more resistant to this infection. Wide investigations for this association may lead to implementation
of a successful effective malaria vaccine program.