Introduction and Objective: The novel coronavirus illness quickly swept the globe. With a high rate of patients presenting severe acute respiratory syndrome, Tunisia is one of the most affected nations but clinical factors associated with COVID-19 mortality among Tunisian hospitalised patients are rarely studied. Our study aimed to identify independent risk factors of hospital COVID-19 mortality in a tertiary care center since the start of the pandemic. Methods: An observational prospective study was conducted among confirmed COVID-19 patients who were hospitalized in Sahloul university hospital between September 2020 and November 2022. To identify risk factors of hospital COVID-19 mortality, Kaplan Meier survival analysis and Cox Proportional Hazard regression were used. Results: A total of 1978 patients were hospitalized in Sahloul University Hospital between September 26th 2020 and November 30th 2022. The mean age was 55.65± 21.39 years [1 – 94]. During the study period, a total of 417 Deaths were reported, with a median survival 30+/- 3.11 days (95% CI [23.904; 36.096]). Mortality was significantly associated with: age (p< 10-3), comorbidities (p= 0.01), obesity (p< 10-3), cardiovascular disease (p =0.015), endocrine pathologies (p= 0.01), obesity (p< 10-3), hospitalization in intensive care units (ICU) (p< 10-3) and Oro tracheal intubation (p< 10-3). At multivariable analyses, hypertension (HR 1.93; CI [1.2; 3.72]), cardiovascular disease (HR 4.11; CI [1.99; 17.09]) and being admitted in ICU (HR 31.49; CI [11.04; 72.9]), were independent associated factors with COVID-19 mortality. Conclusions: The early identification of high-risk COVID-19 patients is mandatory to decrease this virus morbi-mortality. And this can only be reached by multidisciplinary interventions to solve this public health problem.