A cross-sectional, analytical study conducted over a period of 6 months from April to September 2021 after the approval of REC on 50 patients with confirmed positive of COVID-19 by SARS-CoV-2 nucleic acid RT-PCR recruited from Isolation departments and intensive care units (ICUs), Beni-Suef University hospital. The goal of this study was to assess the serum level of (IL-18) as a biomarker of COVID-19 disease progression.  All participants underwent complete blood count (CBC), C- reactive protein (CRP), fibrinogen, D-dimer and liver enzymes and measurement of serum IL- 18 level. All patients had been followed until hospital discharge or death. Forty-two patients (84%) recovered and discharged from the hospital while eight cases (16%) died due to different etiologies: 2 patients due to suppurative lung infection, another 2 because of multi organ failure, 2 patients owing to respiratory failure and alveolar damage, and the last 2 patients with cardiac comorbidity after ischemic heart disease and hypertension. There were a significant higher level of CRP, D-dimer, ferritin, and IL-18 among died as compared with recovered COVID-19 patients. Platelets count was significantly higher among recovered as compared with died COVID-19 patients. Correlation test showed a significant positive strong linear relationship between CRP level and IL-18, D-dimer level, and IL-18, and between ferritin level and IL-18. High values of IL-18 in patients' serum helped to assess the poor prognosis which was statistically significant with 81.5% sensitivity and 57.5% specificity at a cutoff point level ≥ 230.75. Elevated serum levels of IL-18 were associated with fatal outcome in the COVID-19 infected patients and showed strong correlation with other inflammatory markers.