Inclusion Criteria:

• Must have a documented traumatic brain injury (TBI), defined as damage to brain tissue caused by an external mechanical force as evidenced by: loss of consciousness due to brain trauma, or post traumatic amnesia (PTA), or skull fracture, or objective neurological findings that can be reasonably attributed to TBI on physical examination or mental status examination.
• Age 18 years or older
• At least three months postinjury
• Presence of major depressive disorder (MDD), as defined by Structured Clinical Interview for DSM-IV (SCID) interview
• Hamilton Depression Rating Scale (Ham-D) scores of 18 or greater on two consecutive evaluations (screening and baseline)

Exclusion Criteria:

• Individuals under 18 years of age
• Pregnancy, as determined by urine pregnancy screen
• Prisoners
• Individuals who are institutionalized
• Individuals who are not cognitively capable of completing the SCID interview and the Ham-D
• Unstable medical condition, defined as any significant medical condition likely to require hospitalization during the study period, or requiring adjustment in medications in the past month
• Active suicidality
• Severe depression that, in the investigator's professional opinion, will likely require hospitalization during the study time period
• Diagnosis of bipolar disorder, as defined by SCID interview
• Diagnosis of schizophrenia or other psychotic disorder, as defined by SCID interview, other than major depression with psychotic features
• Active drug or alcohol abuse within the past 3 months, as defined by SCID interview
• Dysphagia sufficient to preclude use of oral medications
• Known hypersensitivity to venlafaxine
• Use of monamine oxidase inhibitors (MAOI) within the past month
• Treatment with antidepressant medication within the past 3 months
• Concomitant administration of medications that interact with venlafaxine to a clinically significant degree