The combination of hyperbaric oxygen therapy (HBO) and recombinant tissue-plasminogen activator (tPA) is of interest in the treatment of acute ischemic stroke with a view to combine positive effects of both strategies. We investigated neurological and functional outcome after early treatment with HBO additional to tPA in ischemic stroke. Focal cerebral ischemia was induced using an embolic stroke model in 87 male Wistar rats. Animals were randomized to therapy with tPA+HBO, tPA alone, or control. Menzies score, Beam walk, and the Corner test were assessed for a period of 4 weeks following ischemia. Within the first 24 h neurological deficits improved in all groups but most pronounced in animals treated with tPA+HBO. Thereafter, a deterioration of neurological deficits occurred in the tPA+HBO group with significant differences at day 7, 8, 18, and 24 (P<0.05). Surprisingly, Beam walk and Corner test results did not differ significantly between all groups. This first report of early simultaneous treatment with tPA and HBO in experimental embolic stroke with 4-week follow-up confirms previous studies reporting positive effects of HBO shortly after the ischemia. Following the acute phase, combined tPA and HBO resulted in deterioration of neurological deficits without affecting functional recovery. Future studies should focus on interactions of tPA and HBO on molecular level leading to delayed damage to brain tissue at risk. Michalski, Küppers-Tiedt, Weise, Laignel, Härtig, Raviolo, Schneider, Hobohm, (2009). Long-term functional and neurological outcome after simultaneous treatment with tissue-plasminogen activator and hyperbaric oxygen in early phase of embolic stroke in rats. Brain research, 2009 Dec;1303():161-8. https://www.ncbi.nlm.nih.gov/pubmed/19766603