Two successive COVID-19 flares occurred in Switzerland in spring and autumn 2020. During these periods, therapeutic strategies have been constantly adapted based on emerging evidence. We aimed to describe these adaptations and evaluate their association with patient outcomes in a cohort of COVID-19 patients admitted to the hospital. Consecutive patients admitted to the Geneva Hospitals during two successive COVID-19 flares were included. Characteristics of patients admitted during these two periods were compared as well as therapeutic management including medications, respiratory support strategies and admission to the ICU and intermediate care unit (IMCU). A mutivariable model was computed to compare outcomes across the two successive waves adjusted for demographic characteristics, co-morbidities and severity at baseline. The main outcome was in-hospital mortality. Secondary outcomes included ICU admission, Intermediate care (IMCU) admission, and length of hospital stay. A total of 2'983 patients were included. Of these, 165 patients (16.3%, n = 1014) died during the first wave and 314 (16.0%, n = 1969) during the second (p = 0.819). The proportion of patients admitted to the ICU was lower in second wave compared to first (7.4 vs. 13.9%, p < 0.001) but their mortality was increased (33.6% vs. 25.5%, p < 0.001). Conversely, a greater proportion of patients was admitted to the IMCU in second wave compared to first (26.6% vs. 22.3%, p = 0.011). A third of patients received lopinavir (30.7%) or hydroxychloroquine (33.1%) during the first wave and none during second wave, while corticosteroids were mainly prescribed during second wave (58.1% vs. 9.1%, p < 0.001). In the multivariable analysis, a 25% reduction of mortality was observed during the second wave (HR 0.75; 95% confidence interval 0.59 to 0.96). Among deceased patients, 82.3% (78.2% during first wave and 84.4% during second wave) died without beeing admitted to the ICU. The proportion of patients with therapeutic limitations regarding ICU admission increased during the second wave (48.6% vs. 38.7%, p < 0.001). Adaptation of therapeutic strategies including corticosteroids therapy and higher admission to the IMCU to receive non-invasive respiratory support was associated with a reduction of hospital mortality in multivariable analysis, ICU admission and LOS during the second wave of COVID-19 despite an increased number of admitted patients. More patients had medical decisions restraining ICU admission during the second wave which may reflect better patient selection or implicit triaging.