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BACKGROUND The Hybrid emergency room (ER) system is a novel trauma workflow that uses angio-computed tomography (CT) equipment in a trauma resuscitation room. Although the Hybrid ER system decreases time to start surgery and endovascular treatments and improves mortality, the optimal target benefitting from this system remained unclear. We aimed to identify a subset of trauma patients likely to receive the greatest benefits from the Hybrid ER. MATERIAL AND METHODS This retrospective cohort study was conducted in a tertiary hospital in Japan from August 2007 to January 2020. We consecutively included severe adult blunt trauma patients (Injury Severity Score [ISS] ≥16) and divided them into two groups: Conventional group (August 2007-July 2011) and Hybrid ER (August 2011-January 2020) group. We evaluated the association between the Hybrid ER group and 28-day mortality using multivariable logistic regression analysis. The 28-day mortality trend during the study period was evaluated with restricted cubic spline analysis. To evaluate heterogeneity of effects within various patient severities, we evaluated whether the patients' ISS modified the effect of the Hybrid ER on survival. RESULTS Among 1050 trauma patients, the Conventional group comprised 360 and Hybrid ER group 690 patients. ISS and probability of survival (Ps) were not significantly different between the groups. Twenty-eight-day mortality was significantly lower in the Hybrid ER group (Ps-adjusted odds ratio, 0.48; 95% confidence interval, 0.32-0.71; p<0.001). Restricted cubic spline analysis revealed that Ps-adjusted 28-day mortality sharply decreased approximately 200 days after installation of the Hybrid ER. Increase of survival probabilities according to the increase of ISS was significantly improved in Hybrid ER group (p=0.014). As ISS increased to >25, survival probabilities in the Hybrid ER group were higher compared with those in the Conventional group. CONCLUSION The Hybrid ER may improve post-traumatic mortality, especially in patients with higher baseline severity. LEVEL OF EVIDENCE Level-III.