Background: Asthma is chronic immune-mediated airway inflammation, and it is affected by a complex network of interacting cytokines. To date, the exact role of each cytokine and its genetic polymorphisms in childhood asthma development and its severity has remained poorly understood. The purpose of this study was to explore potential roles of four cytokine genes polymorphism and serum levels l [(T helper-2 (Th2) cytokine); Interleukin- 4 (IL-4) 590, (Th3 cytokine); and transforming growth factor β1 (TGF-β1) 509T; (Th17) including tumor necrosis factor-alpha (TNF-α), and IL17A rs8193036] in childhood asthma risk and control in Egyptian children, for the 1st time. Materials and methods: This case-control study included two children subgroups; Group1 included 216 nonasthmatic controls and (Group 2) 216 cases diagnosed with asthma (clinically and spirometry-based) were classified as controlled, partly controlled, and uncontrolled. Polymorphisms of TGF-β1-509, IL-4 590, and TNF- α-308 genes were detected using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP). IL-17 was genotyped using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Serum cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Serum total IgE, TGF-β1, IL4, TNF-α, and IL17A levels were significantly higher in asthmatic compared to controls. Also, significant increases in serum total IgE, IL-4, TGF-β1, and TNF-α levels are combined with poor asthma control, while no significant IL17A changes. There were significant changes of IL-4-590, TNF-α-308, and IL17A genotypes and allele distributions between asthmatic and controls groups as well as different asthma control levels; while no impact of TGF-β1 SNP on asthma risk and control level. Four cytokines SNPs affected their serum levels among asthmatic patients. Conclusion: There are impacts of cytokine gene polymorphisms (IL-4-590, TNF-α-308, and IL17A); but not TGF-β1 on asthma susceptibility and poor asthma control in Egyptian children.