Acute physical injury is frequently associated with mental health sequelae, which then accentuate disability and worsen functional outcomes. A pharmacological prevention approach to this problem has been proposed. This proof-of-concept study was a double-blind, randomized controlled trial of 14 days of the beta-blocker propranolol (n = 17), the anxiolytic anticonvulsant gabapentin (n = 14), or placebo (n = 17), administered within 48 hours of injury to patients admitted to a surgical trauma center. Of 569 accessible, potentially eligible subjects, 48 (8%) participated. Outcomes assessments were conducted at 1, 4, and 8 months postinjury. Although well tolerated, neither study drug showed a significant benefit over placebo on depressive or posttraumatic stress symptoms. Implications are discussed for future pharmacological prevention studies in survivors of acute traumatic injury.