Introduction: Little evidence suggest that female gender is associated with a lower risk of mortality in severely injured patients, especially in premenopausal women. Previous clinical studies have shown contradictory results regarding protective effects of gender on outcome after severe trauma. The objective of this study was to determine the association between gender and outcome (mortality and Intensive Care Unit (ICU) admission) among severely injured patients in the Netherlands. Methods: A retrospective multicentre study was performed including all polytrauma patients (Injury Severity Score (ISS) ≥16) admitted to the ED of three level 1 trauma centres, between January 1st, 2006 and December 31st, 2014. Data on age, gender, mechanism of injury, ISS, Abbreviated Injury Scale (AIS), prehospital intubation, Revised Trauma Score (RTS), systolic blood pressure (SBP) and Glasgow Coma Scale (GCS) upon admission at the Emergency Department was collected from three Regional Trauma Registries. To determine whether gender was an independent predictor of mortality and ICU admission, logistic regression analysis was performed. Results: Among 6865 trauma patients, male patients had a significantly higher ISS compared to female patients (26.3 ± 10.2 vs 25.3 ± 9.7, P = < 0.0001). Blunt trauma was significantly more common in the female group (95.2% vs 92.3%, P = < 0.0001). Males aged 16- to 44-years had a significant higher in-hospital mortality rate (10.4% vs 13.4%, P = 0.046). ICU admission rate was significantly lower in females (49.3% vs 54.5%, P = < 0.0001). In the overall group, logistic regression did not show gender as an independent predictor for in-hospital mortality (OR 1.020 (95% CI 0.865-1.204), P = 0.811) or mortality within 24 h (OR 1.049 (95% CI 0.829-1.327), P = 0.693). However, male gender was associated with an increased likelihood for ICU admission in the overall group (OR 1.205 (95% CI 1.046-1.388), P = 0.010). Conclusion: The current study shows that in this population of severely injured patients, female sex is associated with a lower in-hospital mortality rate among those aged 16- to 44-years. Furthermore, female sex is independently associated with an overall decreased likelihood for ICU admission. More research is needed to examine the physiologic background of this protective effect of female sex in severe trauma.