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Syncope is a common phenomenon in the general population. Although most of the causes are of benign origin, some comorbidities are accompanied by high mortality. We aimed to compare the in-hospital mortality of patients with syncope related to different comorbities and investigate the impact of syncope in patients with atrial fibrillation/flutter (AF). The nationwide inpatient sample of Germany of the years 2011–2014 was used for this analysis. Patients with syncope (ICD-code R55) were stratified by presence of selected comorbidities. Additionally, AF patients with and without syncope were compared. Incidence of syncope and in-hospital mortality were calculated. Syncope as a predictor of adverse outcome in AF patients was investigated. In total, 1,628,859 hospitalizations of patients with syncope were identified; incidence was 504.6/100,000 citizens/year with case-fatality rate of 1.6%. Patients with syncope revealed frequently comorbidities as AF, heart failure and pneumonia. In-hospital mortality was high in syncope patients with pulmonary embolism (PE, 13.0%), pneumonia (12.8%), myocardial infarction (MI, 9.7%) and stroke (8.5%). We analysed 1,106,019 hospitalizations (52.9% females, 54.9% aged > 70 years) of patients with AF (2011–2014). Among these, 23,694 (2.1%) were coded with syncope and 0.7% died. Syncope had no significant impact on in-hospital mortality (OR 1.04, 95%CI 0.92–1.17, P =.503) independently of age, sex and comorbidities, but was associated with PE (OR 1.83, 95%CI 1.42–2.36, P <.001), MI (OR 1.68, 95%CI 1.48–1.90, P <.001), stroke (OR 1.66, 95%CI 1.42–1.94, P <.001) and pneumonia (OR 1.26, 95%CI 1.16–1.37, P <.001). Syncope is a frequent cause for referrals in hospitals. While the overall in-hospital mortality rate is low (<2%), syncope in coprevalence with PE, pneumonia, MI and stroke showed a mortality rate > 8%. Syncope in AF patients had no independent impact on in-hospital mortality. • Syncope is a frequent cause for referrals in hospitals. • The overall in-hospital mortality was 1.6%. • Syncope in PE, pneumonia, MI and stroke showed an in-hospital mortality rate > 8%. • Syncope in AF patients was accompanied by higher in-hospital mortality. • Syncope did not influence the risk to die in-hospital independently in AF patients. [ABSTRACT FROM AUTHOR]