question: Background: Since December 2019, a type of coronavirus has emerged in Wuhan, China, which has become the focus of global attention due to an epidemic of pneumonia of unknown cause, called COVID-19. This study aimed to investigate the factors affecting in-hospital mortality of patients with COVID-19 hospitalized in one of the main hospital in central Iran. Methods This retrospective cross-sectional study (February 2019-May 2020) was conducted on patients with confirmed diagnosis COVID-19, who were admitted in Yazd Shahid Sadoughi Hospital, in middle of Iran. The patients with uncompleted or missed medical files were excluded from the study. Data were extracted from the patients' medical files and then analyzed. The patients were categorized as survivors and non-survivors groups, and they were compared. Results Totally, 573 patients were enrolled, that 356 (62.2%) were male. The mean ± SD of age was 56.29 ± 17.53 years, and 93 (16.23%) were died. All the complications were more in non-survivors. Intensive care unit (ICU) admission was in 20.5% of the patients which was more in non-survivors (P < 0.001). The results of multivariate logistic regression test showed that plural effusion in lung computed tomography (CT) scan (OR = 0.055, P = 0.009), white blood cell (WBC) (OR = 1.417, P = 0.022), serum albumin (OR = 0.009, P < 0.001), non-invasive mechanical ventilation (OR = 34.315, P < 0.001), and acute respiratory distress syndrome (ARDS) (OR = 66.039, P = 0.001) were achieved as the predictive factors for in-hospital mortality were the predictive factors for in-hospital mortality. Conclusion In-hospital mortality in patients with COVID-19 was about 16%. Plural effusion in lung CT scan, WBC, albumin, non-invasive mechanical ventilation, and ARDS were obtained as the predictive factors for in-hospital mortality.