OBJECTIVES: To compare patient management and outcome during the first and second waves of the coronavirus 2019 pandemic. DESIGN: Single-center prospective cohort study. SETTING: Tertiary-care University Hospital. PATIENTS: All adult patients admitted in either the first (from March 15 to May 15, 2020) or second (from October 1 to November 30, 2020) wave of corona virus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was 30-day mor tality. During the second wave of the coronavirus disease 2019 pandemic, 33 patients (4.8%) were transferred due to overcrowding and excluded from anal ysis. There were 341 (first wave of the coronavirus disease 2019 pandemic) and 695 (second wave of the coronavirus disease 2019 pandemic) coronavirus di sease 2019 patients admitted to the hospital, with median age first wave of the coronavirus disease 2019 pandemic as 68 (57–80) and second wave of the coronavirus disease 2019 pandemic as 71 (60–80) (p = 0.15), and similar admis sion severity. For the first wave of the coronavirus disease 2019 pandemic versus second wave of the coronavirus disease 2019 pandemic, 30-day mortality was 74/341 (22%) and 98/662 (15%) (p = 0.007). In the ward, 11/341 (3.2%) and 404/662 (61%) received dexamethasone (p < 0.001); 6/341 (2%) and 79/662 (12%) received high-flow nasal oxygen (p < 0.0001); 2/341 (0.6%) and 88/662 (13.3%) received remdesivir (p < 0.0001); 249/341 (73%) and 0/662 (0%) re ceived hydroxychloroquine (p < 0.0001); and 87/341 (26%) and 128/662 (19%) (p = 0.024) patients were transferred to ICU. On ICU admission, median Sequential Organ Failure Assessment was 6 (3–7) and 4 (3–6) (p = 0.02). High flow nasal oxygen was given to 16/87 (18%) and 102/128 (80%) (p < 0.001); 69/87 (79%) and 56/128 (44%) received mechanical ventilation (p < 0.001) with durations 17 days (10–26 d) and 10 days (5–17 d) (p = 0.01). Median ICU length of stay was 14 days (5–27 d) and 6 days (3–11 d) (p < 0.001). Finally, 16/87 (18%) and 8/128 (6%) received renal replacement therapy (p = 0.0055); and 64/87 (74%) and 51/128 (40%) needed vasopressor support (p < 0.001). CONCLUSIONS: The main therapeutic changes between the first wave of the coronavirus disease 2019 pandemic and the second wave of the coronavirus di sease 2019 pandemic were use of steroids, unrestrictive use of high-flow nasal oxygen for hypoxemic patients, and transfer of patients to other geographic areas in the case of ICU overcrowding. These changes were associated with a de crease in 30-day mortality, ICU admission, and organ support.