(1) Background: Since the onset of the SARS-CoV-2 pandemic, seven epidemic waves have been described in Spain. Our objective was to study mortality and severity, and associated factors in our hospitalized patients; (2) Method: Retrospective cohort study was conducted on COVID-19 patients admitted to the Hospital de Fuenlabrada (Madrid, Spain) from the beginning of the pandemic until December 31, 2022; (3) Results: A total of 5,510 admissions for COVID-19 were recorded. First wave accounted for 1,823 (33%) and exhibited the highest proportion of severe patients (lowest mean oxygen saturation, 88.2%; elevated levels of CRP, IL-6, D-dimer and ferri-tin), but a below-average percentage of intubated patients (5% vs. 6.5%). Overall mortality rate was 10.3%, higher during the first wave (11.5%) and the two winter waves (third: 11.3%, sixth: 12%), although the first wave represented 39% of the total. Variables associated with mortality were age (OR 1.08,1.07-1.09), need for high-flow oxygen (OR 6.10,4.94-7.52), oncological disease (OR 1.88,1.53-2.60), dementia (OR 1.82,1.2-2.75), Charlson index (OR 1.38,1.31-1.47), and maxi-mum IL-6 levels (OR 1.001,1.000-1.001); (4) Conclusions: Variables associated with mortality in-cluded age, comorbidity, respiratory failure, and inflammation. Differences on baseline charac-teristics of patients admitted explained differences on mortality in each wave