INTRODUCTION: Recent studies have underscored the importance of genetic factors in predicting COVID-19 susceptibility and severity. While cytokine storms are crucial in disease severity, genetic predisposition significantly influences immune responses. Our study examined genes related to SARS-CoV-2 invasion (ACE2 rs2074192) and interferon-induced immunity (IFNAR2 rs2236757, TYK2 rs2304256, OAS1 rs10774671, OAS3 rs10735079). Additionally, we investigated genes linked to Kawasaki disease (CD40 rs4813003, FCGR2A rs1801274, CASP3 rs113420705) that play roles in immunogenesis. METHODS: The pilot study, which involved 75 pediatric patients aged one month to 17 years [43 patients with active COVID-19, 17 children with multisystem inflammatory syndrome in children (MIS-C), and 15 healthy controls], was conducted in Ternopil, Ukraine. Gene polymorphism was studied for all patients. ELISA kits were used for interleukin studies, including Human IL-1β (Interleukin 1 Beta), Human IL-6 (Interleukin 6), Human IL-8 (Interleukin 8), Human IL-12 (Interleukin 12), Human IFN-α (Interferon Alpha), and Human TNF-α (Tumor Necrosis Factor Alpha). Statistical analysis was performed using IBM SPSS Statistics 21 and GraphPad Prism 8.4.3. RESULTS: The analysis identified significant gene-cytokine associations in pediatric COVID-19 patients. The ACE2 rs2074192 T allele correlated with increased IL-1β, IL-6, IL-8, and TNF-α. The IFNAR2 rs2236757 A allele was linked to elevated IL-1β and IL-12 levels and low IFN-α levels, while OAS1 rs10774671 A allele carriers also exhibited lower IFN-α levels. OAS1 rs10774671 was prognostically crucial for determining IL-8 levels in children infected with SARS-CoV-2. OAS3 gene polymorphism rs10735079 was associated with changes in IL-6 levels, precisely a high level. The CD40 rs4813003 T allele increased IFN-α levels, while carriers of allele C had higher levels of IL-12. The results of our study revealed a correlation between IL-8 levels and the FCGR2A gene polymorphism rs1801274 (A/G). The CASP3 gene polymorphism rs113420705 led to an increase in IL-6. CONCLUSION: These findings enhance our understanding of pediatric COVID-19 and may hold promise for developing targeted interventions and providing a personalized medical approach for each patient.