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Background: Identifying risk factors for complications or death associated with influenza remains crucial to target preventive interventions. Scores like the Charlson comorbidity index (CCI) may be of help. The aims of this study were to assess the effect of vaccination and comorbidities on severe influenza disease and influenza-related death among hospitalized patients during the season 2016/17; and to evaluate the validity of the CCI to predict death among these patients. Methods: Data from adult patients (≥18 years old) with influenza infection admitted to La Paz University Hospital (LPUH) were recorded during the 2016/17 epidemic. The effect of influenza vaccine to prevent severe influenza or death was evaluated using multivariate logistic regression models. The area under the curve of the CCI and the age-adjusted CCI were compared to assess the predictive effect on mortality. Results: A total of 342 adult patients with influenza infection were admitted, of which 83 developed severe influenza and 25 died during hospitalization. There were no differences between patients who survived and those who died concerning the CCI, but the age-adjusted CCI was higher in fatal cases (p-value = 0.005). Influenza vaccine had no statistically significant effect on the risk of mortality (p-value = 0.162) while age (OR: 1.12, p-value