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The high incidence of persistent postconcussion symptoms in service members with combat-related mild traumatic brain injury has prompted research in the use of hyperbaric oxygen (HBO2) for management.The effects of HBO2 on persistent postconcussion symptoms in 60 military service members with at least 1 combat-related mild traumatic brain injury were examined in a single-center, double-blind, randomized, sham-controlled, prospective trial at the Naval Medicine Operational Training Center at Naval Air Station Pensacola.Over a 10-week period, subjects received a series of 40, once-daily, hyperbaric chamber compressions at 2.0 atmospheres absolute (ATA). During each session, subjects breathed 1 of 3 preassigned oxygen fractions (10.5%, 75%, or 100%) for 60 minutes, resulting in an oxygen exposure equivalent to breathing surface air, 100% oxygen at 1.5 ATA, or 100% oxygen at 2.0 ATA, respectively. Individual, subscale and total item responses on the Rivermead Postconcussion Symptom Questionnaire and individual and total Posttraumatic Disorder Checklist–Military Version were measured just prior to intervention and immediately postintervention.Between-group testing of pre- and postintervention means revealed no significant differences on individual or total scores on the Posttraumatic Disorder Checklist–Military Version or Rivermead Postconcussion Symptom Questionnaire, demonstrating a successful randomization and no significant main effect for HBO2 at 1.5 or 2.0 ATA equivalent compared with the sham compression. Within-group testing of pre- and postintervention means revealed significant differences on several individual items for each group and difference in the Posttraumatic Disorder Checklist—Military Version total score for the 2.0 ATA HBO2 group.The primary analyses of between group differences found no evidence of efficacy for HBO2. The scattered within group differences are threatened by Type 2 errors and could be explained by nonspecific effects.This study demonstrated that HBO2 at either 1.5 or 2.0 ATA equivalent had no effect on postconcussion symptoms after mild traumatic brain injury when compared with sham compression.