We conducted a single-center retrospective study to compare patient characteristics and death rates during the Omicron (O, December 01, 2021, to September 30, 2022) and pre-Omicron (PO, March 01, 1920, to October 31, 2021) periods. We retrospectively analyzed the data of 2932 patients (1242 (O) and 1690 (PO)) hospitalized (>24 h) with laboratory-confirmed COVID. Compared to the PO period, O period patients were less frequently men, had a lower body mass index and fewer comorbidities except for immunosuppression and pregnancy. Nosocomial COVID-19 accounted for 18.2 % (O) and 15.4 % (PO) of cases (p = 0.05). Patient mortality rates during the O and PO periods were 11.0 % and 16.9 % (p < 0.001), respectively. Unvaccinated status (p < 0.001), existence of comorbidities, (p < 0.001) and high LDH value at baseline (p = 0.015), but not the period, were identified as factors likely to explain death. During the Omicron period, the inpatient death rate remained > 10 %, especially among unvaccinated and comorbid patients. Nosocomial cases were more frequent.