Background: Malaria, a disease with a wide variation in clinical presentation (ranging from mild to deadly cerebral malaria) remains an important health challenge in the tropics including Sudan. This study investigates the role of allelic single nucleotide polymorphism in Promoter regions (-590 C/T) of the IL-4 genes, Serum IL-4, IgE and TNF-concentrations in severity of malaria in Sudanese children. Methods: This is hospital based- case control cross-sectional study on one hundred ten malaria patients and sixty healthy controls. The blood samples were assessed for IL-4, IgE and TNF-α using enzyme-linked immunosorbent assay (ELISA) technique. Extracted DNA and ready use master mix were used in polymerase chain reaction, then the product was digested by BSMFI restriction enzyme. Results: IL-4 SNP was found to have a significant association with the development of cerebral malaria. Allele frequency was CT % = 50:50 (p = 0.03). Results shows a significant difference (p= 0.003) in IL-4 concentration when compared with allele genotypes in cerebral malaria patient, the highest concentration was shown in the allele TT (363.0 ± 199.5 Pg/ml).IL-4 level in uncomplicated malaria patients revealed a significant difference between groups (p= 0.009), the highest concentration was for mutant allele CT (428.4 ± 101.1 Pg/ml). Conclusion: Our study suggests that IL-4 (-590 C/T) gene polymorphism is associated with the severity of Plasmodium falciparum malaria infection in Sudanese children. IL-4 SNP was found to have a significant association with the development of cerebral malaria and with increased levels of serum IL-4.