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Background: Hyperglycemia following trauma could be a response to stress. The constellation of the initial hyperglycemia, proinflammatory cytokines and severity of injury among trauma patients is understudied. We aimed to evaluate the patterns and effects of on-admission hyperglycemia and inflammatory response in a level 1 trauma center admissions. Methods: A prospective, observational study was conducted for adult trauma patients who were admitted and tested for on-admission blood glucose, hemoglobin A1c, interleukin (IL)-6 ,Il-18 and hs-CRP. Patients were categorized into 4 groups (non-diabetic normoglycemic, diabetic normoglycemic, diabetic hyperglycemic (DH) and stress-induced hyperglycemic (SIH)). The inflammatory markers were measured on 3 time points (admission, 24 h, and 48 h). Pearson’s correlation test and logistic regression analysis were performed. We hypothesized that higher initial readings of blood glucose and cytokines are associated with severe injuries and worse in-hospital outcomes in trauma patients.Results: During the study period, 250 adult trauma patients were enrolled. Almost 13% of patients presented with hyperglycemia (SIH&DH); of whom 50% had SIH. Compared to the other 3 groups; SIH patients were younger, had significantly higher ISS, higher IL-6 readings, prolonged hospital length of stay and higher mortality. The SIH group had lower Revised Trauma Score (p=0.005), lower Trauma Injury Severity Score (p=0.01) and lower GCS (p=0.001). IL-18 and hs-CRP were comparable among the study groups. Compared to the normoglycemia groups, patients with hyperglycemia had elevated high- sensitive troponin T (p=0.001) and required more blood transfusion (p=0.03). Patients with hyperglycemia had 3-times higher in-hospital mortality than the normoglycemia groups (p=0.02). A significant correlation was identified between initial blood glucose and serum lactate, IL-6, ISS and hospital length of stay. IL-6 correlated well with ISS (r=0.40, p=0.001). On- admission blood glucose had age-sex-GCS adjusted odd ratio 1.20(95% CI 1.06-1.33, p=0.003) for severe injury (ISS≥16).Conclusions: On-admission hyperglycemia is associated with a significant severer injury than normoglycemia patients. Initial blood glucose correlates with serum IL-6 which indicates a potential role of the systemic inflammatory response in the disease pathogenesis among the injured patients. On-admission glucose level could be a useful marker of injury severity, triage and risk assessment in trauma patients.This study was registered at the ClinicalTrials.gov (Identifier: NCT02999386), retrospectively Registered on December 21, 2016 https://clinicaltrials.gov/ct2/show/NCT02999386.