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Chronic diseases are increasing worldwide. Association of two or more chronic conditions is related with poor health status and reduced life expectancy, particularly among elderly patients. Comorbidities represent a risk factor for adverse events in several critical illnesses. We aimed to evaluate if elderly patients are affected by multiple chronic pathologies, assessed by Charlson comorbidity index (CCI), showed a reduced in-hospital survival after ischemic stroke. In a 3-year period, we evaluated all the subjects admitted to our internal medicine department for ischemic stroke. Age, sex, NIHSS score and all the comorbidities were recorded. Days of hospitalization, hospital-related infections and in-hospital mortality were also assessed. For each patient, we evaluated CCI, obtaining four classes: group 1 (CCI: 2-3), group 2 (CCI: 4-5), group 3 (CCI: 6-7) and group 4 (CCI: ≥8). Survival was evaluated with Kaplan-Meier and Cox regression analyses. The complete model considered in-hospital death as the main outcome, days of hospitalization as the time variable and CCI as the main predictor, adjusting for NIHSS, sex and nosocomial infections. Patients in CCI group 3 and 4 had an increased risk of in-hospital mortality, independently of NIHSS, sex and nosocomial infections. Elderly patients with multiple comorbidities have higher risk of in-hospital death when affected by ischemic stroke.