ABSTRACT: Trauma patients with an ISS=75 have been deliberately excluded from some trauma studies because they were assumed to have "unsurvivable injuries." This study aimed to assess the true mortality among patients with an ISS=75, and to examine the characteristics and primary diagnoses of these patients. Retrospective review of the 2006-2010 U.S. Nationwide Emergency Department Sample (NEDS) generated 2,815 patients with an ISS=75 for analysis, representing an estimated 13,569 patients in the country. Dispositions from the emergency department and hospital for these patients were tabulated by trauma center level. Survivors and non-survivors were compared using Pearson's chi-square test. Primary diagnosis codes of these patients were tabulated by mortality status. Overall, about 48.6% of patients with an ISS=75 were discharged alive, 25.8% died and 25.6% had unknown mortality status. The mortality risks of these patients did not vary significantly across different levels of trauma centers (15.6% vs. 13.0%, P = 0.16). Non-survivors were more likely than survivors to: be male (81.2% vs. 74.4%, P < 0.0001), be over 65 years (20.3% vs. 10.2%, P < 0.0001), be uninsured (33.8% vs. 19.1%), have at least one chronic condition (58.0% vs. 43.7%, P <0.0001), sustain life-threatening injuries (79.2% vs. 49.4%, P<0.0001), sustain penetrating injuries (42.0% vs. 25.9%, P<0.0001), and have injuries caused by motor vehicle crashes (32.9% vs. 21.1%, P<0.0001) or firearms (21.9% vs. 4.4%, P<0.0001). The most frequent diagnosis code was 862.8 (injury to multiple and unspecified intrathoracic organs, without mention of open wound into cavity). Our results revealed that at least half of patients with an ISS=75 survived, demonstrating that the rationale for excluding patients with an ISS=75 from analysis is not always justified. To avoid bias and inaccurate results, trauma researchers should examine the mortality status of patients with an ISS=75 before exclusion, and explicitly describe their method of generating ISS scores.