BACKGROUND: An association between stress-induced hyperglycemia (SIH) and increased mortality has been demonstrated following trauma. Experimental animal model data regarding the association between hyperglycemia and outcomes following traumatic brain injury (TBI) are inconsistent, suggesting that hyperglycemia may be harmful, neutral, or beneficial. The purpose of this study was to examine the effects of SIH versus diabetic hyperglycemia (DH) on severe TBI. METHODS: Admission glycosylated hemoglobin (HbA1c), glucose levels, and comorbidity data were collected during a 4-year period from September 2009 to December 2013 for patients with severe TBI (i.e., admission Glasgow Coma Scale [GCS] score of 3-8 and head Abbreviated Injury Scale [AIS] score ≥ 3). Diabetes mellitus was determined by patient history or admission HbA1c of 6.5% or greater. SIH was determined by the absence of diabetes mellitus and admission glucose of 200 mg/dL or greater. A Cox proportional hazards model adjusted for age, sex, injury mechanism, and Injury Severity Score (ISS) was used to calculate hazard ratios (HRs) and associated 95% confidence intervals (CIs) for the association between SIH and the outcomes of interest. RESULTS: During the study period, a total of 626 patients were included in the study group, having severe TBI defined by both GCS score of 3 to 8 and head AIS score being 3 or greater and also had available HbA1c and admission glucose levels. A total of 184 patients were admitted with hyperglycemia; 152 patients (82.6%) were diagnosed with SIH, and 32 patients (17.4%) were diagnosed with DH. When comparing patients with severe TBI adjusted for age, sex, injury mechanism, ISS, Revised Trauma Score (RTS), and lactic acid greater than 2.5 mmol/L, patients with SIH had a 50% increased mortality (HR, 1.49; 95% CI, 1.13-1.95) compared with the nondiabetic normoglycemia patients. DH patients did not have a significant increase in mortality (HR, 0.94; 95% CI, 0.56-1.58). CONCLUSION: SIH is associated with higher mortality after severe TBI. This association was not observed among patients with DH, which suggests that hyperglycemia related to diabetes is of less importance compared with SIH in terms of mortality in the acute trauma and TBI patient. Further research is warranted to identify mechanisms causing SIH and subsequent worse outcomes after TBI. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, leve III.