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Comparing pandemic waves could aid in understanding the evolution of COVID-19. The objective of the present study was to compare the characteristics and outcomes of patients hospitalized for COVID-19 in different pandemic waves in terms of severity and mortality. We performed an observational retrospective cohort study of 5,220 patients hospitalized with SARS-CoV-2 infection from February to September 2020 in Aragon, Spain. We compared ICU admissions and 30-day mortality, clinical characteristics, and risk factors of the first and second waves of COVID-19. The SARS-CoV-2 genome was also analyzed in 236 samples. Patients in the first wave (n = 2,547) were older (median age 74 years [IQR 60–86] vs. 70 years [53–85]; p < 0.001) and had worse clinical and analytical parameters related to severe COVID-19 than patients in the second wave (n = 2,673). The probability of ICU admission at 30 days was 16% and 10% (p < 0.001) and the cumulative 30-day mortality rates 38% and 32% in the first and second wave, respectively (p = 0.007). Survival differences were observed among patients aged 60 to 80 years. We also found some variability among death risk factors and the viral genome between waves. Therefore, the two analyzed COVID-19 pandemic waves were different in terms of disease severity and mortality. [ABSTRACT FROM AUTHOR]