BACKGROUND: The COVID-19 pandemic caused by SARS-CoV-2 is influenced by genetic and epigenetic factors, including miR-155, which affects immune cell and virus functions and laboratory biomarkers. OBJECTIVE: T0 evaluates miR-155’s role as a biomarker for SARS-CoV-2 detection and monitoring, examining its significance in identifying infection in both vaccinated and unvaccinated individuals using ROC curve analysis. METHODS: Blood samples were collected from 70 patients who attended Medical City Hospital in Baghdad from June 2022 to April 2023 and were determined to be associated with SARS-CoV-2 (35 patients were hospitalized at the Intensive Care Units due to the severity of their symptoms while the other 35 were left hospital upon treatment.). Additionally, 35 samples were collected as a healthy control group. RESULTS: The expression level of miR-155 in the serum of samples showed a high level (fold change: 9.81 ± 5.50) in the severe patients’ group in comparison with the moderate patients’ group (fold change: 4.17 ± 2.93) and healthy group (fold change: 1.08 ± 0.01). To assess the performance of miR-155 and laboratory biomarkers, a (ROC) curve was utilized to determine the sensitivity and specificity. CONCLUSIONS: The miR-155 gene, overexpressed in SARS-CoV-2 patients, correlates with disease activity and severity, potentially serving as a biomarker for diagnosis and a potential therapeutic target.