Abstract Background: The new coronavirus causes many respiratory illnesses in Wuhan, China, under the name severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from December 2019. The illness of coronavirus disease 2019 (COVID-19) was brought on by this virus. At least three isoforms of the SP110 nuclear body protein are encoded by the SP110 gene. These include the SP110a, b, and c isoforms, which are the most abundant and are thought to come from alternative mRNA splicing. Aim: This study attempted to evaluate the impact of Sp110 gene variation on COVID-19 susceptibility in the province of Babylon. Materials and Methods: In this study, of 113 cases, 63 cases have clinical symptoms of COVID-19 patients and 50 blood samples were collected from healthy people as a control group in this study from November 2021 to February 2022 at Al-Morgan Hospital. There were many demographic data included in the present study such as age distribution, sex distribution, and geographic distribution of COVID patients. Samples (63) from suspected COVID-19 patients from different age groups ranging from 20 to 80 years old were considered. Results: The Sp110 rs7580900 AA genotype was the most frequent in both COVID-19 (28.32%) and control (21.24%) groups. This indicates that the Sp110 Rs7580900 single-nucleotide polymorphisms are not related to susceptibility to COVID-19 in patients (P ≤ 0.05). Conclusion: Significant results were seen in SP110 gene polymorphism between COVID patients and vaccinated persons at P ≤ 0.05. This may be the of Sp110in mediating SARS-CoV-2 infection as a novel route for SARS-CoV-2 entry.