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Literature lacks on sex differences in acute pulmonary embolism (PE). Therefore, the aim of our study was to provide information about sex difference in thromboembolic burden, prognostic assessment and outcomes of PE.We analyzed and compared differences between females and males retrieving data of a multicenter, observational, retrospective, cohort study aimed to analyze characteristics of PE patients admitted in Internal Medicine wards of Tuscany, Italy.272 (60.1%) of 452 patients enrolled in the study were females. Females were older than males (76.6 ± 12.0 vs. 73.5 ± 13.4 years, p = 0.0005). Mean length of hospital stay was longer in females (11.3 vs. 9.5 days, p = 0053). Reduced mobility was more frequent in females (46.3% vs. 35.5%, p = 0.0322), whereas COPD and active cancer were in males (20% vs. 9.9%, p = 0.0034, and 39.4% vs. 23.8%, p = 0.0004, respectively). Incidental diagnosis of PE was performed more often in males compared to females (19.3% vs. 11.4%, p = 0.0289). No sex difference was found in diagnostic approach, despite females underwent more often to legs ultrasonography compared to males (90.7% vs. 79.4%, p = 0.0008). Both all cause and PE-related mortality were higher in males (12.2 and 8.3% vs. 7.7 and 5.1%, respectively), despite difference was not significant. Females were found to have more likely central PE and distal deep vein thrombosis compared to males (57.7% vs. 43.8%, p = 0.0039, and 22.9% vs. 13.9%, p = 0.0206, respectively). None difference was found in shock index and median simplified PESI score between females and males, whereas according to 2008 ESC prognostic model females were more likely to be categorized at high or intermediate risk than in males (81.5% vs. 71.5%, p = 0.0159). Echocardiographic right heart dysfunction was found more often in females than in males (56.5% vs. 44%, p = 0.0124). No sex difference was found neither on acute treatment nor in prescription of vitamin K antagonists at hospital discharge. Bleeding events were significantly higher in females compared to males (4.7% vs. 0.5%, p = 0.0189).Understanding the difference between females and males is of utmost importance for physicians who manage acute PE in clinical practice. Females present major pulmonary thromboembolic burden, more frequently right heart dysfunction and treatment-related bleedings but lower in-hospital mortality than males. Our study could implicate that management of acute PE should be tailored according to sex. Prospective studies are warranted to better clarify this topic.