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Purpose: This study investigated the clinical determinants of mortality in hospitalized patients infected with COVID-19. Patients and Methods: A retrospective multicenter large cohort of COVID-19 patients hospitalized between March 2020 and February 2021. We included patients admitted with a confirmed COVID-19 infection with positive COVID-19 through real-time polymerase chain reaction (RT-PCR). SPSS version 25.0 (Armonk, NY: IBM Corp.) was used to analyze the data. Results: Among the study participants (n = 1444), the mean age of the population was 49.22± 17.69 years, of which 63.9% were males (n = 924). Overall, the mean age for non-survivors was 55.65 ± 16.41 years and the length of ICU stay was 13.95 ± 12.4 years. The most common comorbidity among the study subjects was hypertension (HTN) (32.7%), followed by cardiovascular disease (CVD) (10.7%). Patients who were mechanically ventilated (MV) had higher mortality than those who did not require MV (p < 0.001). Conclusion: Our study concluded that old age, the presence of underlying cardiovascular conditions, an abnormal WBC count (leukopenia or leukocytosis), and abnormal blood urea nitrogen (BUN) levels are among the independent predictors of mortality in the Saudi population. These findings may guide health care providers to manage COVID-19 patients more effectively with better outcomes. [ABSTRACT FROM AUTHOR]