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Objective: To understand how pre-injury health status present five-years preceding traumatic brain injury (TBI) affects direct medical cost two years post-injury. Methods: Patients age ≥19 years in the emergency department (ED) or acute care for a TBI between April 1, 2007 and March 31, 2014 in Ontario, Canada (N = 55,669) were identified from population-based health administrative data. Forty-three factors of pre-injury health status (i.e., comorbidities and personal, social, and environmental factors) that were internally validated for the TBI population were assessed in this study. The outcome of interest was direct medical cost within two years of discharge. Sex-specific multivariable linear regressions were conducted to understand the associations between direct medical cost within two years of discharge and pre-injury health status. Results: Patients who received care in the ED (81.9% of total sample) incurred a median cost of $2,492/male patient (average $12,342/patient) and $3,508/female patient (average $65,285/patient) within two years of injury; 37 pre-injury factors were significantly associated with increased direct medical costs. Patients who first received care for their TBI in acute care (18.1%) incurred a median cost of $25,081/male patient (average $63,060/patient) and $30,277/female patient (average $65,285/patient) within two years of injury; 21 factors were significantly associated with increased direct medical costs. Among more prevalent factors, those associated with increased medical cost by at least 50% included mental health disorders, substance abuse, disorders or medical conditions frequently observed among the elderly, cardiovascular disorders, stroke and emergencies involving the brain, metabolic disorders and abdominal symptoms, conditions and symptoms of abdomen and pelvis, genitourinary disorders and disorders of prostate, and pulmonary abdominal and other emergencies. Conclusions: Direct medical costs two years post-TBI differed significantly between patients with and without adverse pre-existing health status. Interdisciplinary teams to promote early identification of pre-existing health conditions and appropriate management and integration of these conditions in TBI care across the continuum of healthcare may be opportunities to reduce direct medical costs post-injury. [ABSTRACT FROM AUTHOR]