The primary objectives of this study are to assess whether participants with traumatic brain injury (TBI) administered glyburide begun within 10 hours of injury will show a decrease in magnetic resonance imaging (MRI)-defined edema and/or hemorrhage, compared to placebo and to assess the safety and tolerability of glyburide compared to placebo in participants with TBI. The secondary objectives include analyzing brain cell loss, computerized tomography (CT) scan /MRI abnormalities, reduction of mortality and or improvement of function or physiology, incidence of decompression craniectomy, incidence of neuroworsening, and to assess the steady state concentrations of glyburide in TBI participants.

Inclusion Criteria:

1. Documented closed head TBI
2. Clearly defined time of injury no more than 10 hours before administration of study drug/placebo
3. GCS 4-14. The GCS will be obtained free of the effects of sedating and/or paralytic drug. Complicated mild must have GCS 13-14 and one or more of the following: Intraparenchymal clots or contusions in aggregate > 10cc; Midline shift > 5mm; IVH, SDH, EDH seen on more than one CT scan slice.
4. Age 18-75 years
5. Patients in whom a dedicated peripheral IV line can be placed for study drug administration
6. Written consent obtained from legally authorized representative (LAR)

Exclusion Criteria:

1. No documented TBI or time of impact not certain
2. Penetrating brain injury
3. Spinal column instability and/or spinal cord injury with neurodeficit
4. Concomitant severe non survivable injury
5. Pregnant, or a positive pregnancy test
6. Women who intend to breastfeed during Study Days 1-4.
7. Blood glucose <50mg/dL
8. Severe renal disorder from the patient's history (e.g. dialysis) or serum creatinine of > 2.5 mg/dL
9. Severe liver disease or total bilirubin >1.5 times upper limit of normal
10. INR>1.4
11. Systolic BP<90 mm Hg not responsive to fluid resuscitation
12. Blood alcohol > 250mg/dL
13. Inability to have MRI (pacemaker, non-MR compatible pressure monitor, etc.)
14. Hospitalization for brain injury, psychiatric or neurological disease within previous 3 years
15. Emergent or urgent surgical operation anticipated (in OR, bedside procedures excluded) that would prevent dosing with study drug within 8 hours of injury.
16. Known use of Coumadin (warfarin), Plavix (clopidogrel), Effient (prasugrel) or Pletal (cilostazol), heparin, low molecular weight heparin, heparinoids, or abciximab or similar antiplatelet agents in the previous 72 hours (Note that patients later found to have taken these medications will not be automatically excluded from the study.)
17. Use of sulfonylurea drugs within the prior 30 days
18. Treatment with another investigational drug within the prior 30 days
19. Allergy to sulfonylurea drugs
20. Known diagnosis of G6PD enzyme deficiency
21. PaO2 < 60 mm Hg on admission (for patients in whom blood gases are drawn per standard of care)
22. Non-English speaking legally authorized representative and subjects (University of Maryland only)
23. Prisoners or others who may be unable to make a truly voluntary and uncoerced decision whether or not to participate in the study
24. Any other clinical condition which in the opinion of the investigator makes the patient unsuitable for inclusion into the study