The main goal in the treatment of acute ischemic stroke is prompt arterial recanalization. Thrombolysis with recombinant tissue plasminogen activator (rtPA) is efficient in humans, but shows significant problems including stow and incomplete recanalization and frequent bleeding complications. Limited therapeutic window (the first three hours after onset) is the major limitation resulting in reach too few patients. Therefore, adjunctive therapies extending the reperfusion time window, increasing efficacy and reducing side effects of rtPA are needed. Ultrasound augmentation of rtPA-mediated thrombolysis is suggested to overcome some of these problems, but low-frequency ultrasound (less than 1 MHz) is not safe and high frequency ultrasound (2 MHz) is not much effective. We suggest that normobaric hyperoxia (NBO) may increase the efficacy of ultrasound and rtPA combination in addition to its own efficacy in acute ischemic stroke. Briefly, NBO increases arterial partial oxygen pressure (pO(2)) significantly up to 6-fold. Increase Of pO(2) results in an increase of dissolved oxygen in the blood according to Henry's law. Enhanced dissolved oxygen increases gas nuclei formation around and inside of the clot, and decreases the Blake threshold. Under ultrasound field, these small gas nuclei form nanobubbles which fuel inertial cavitation as substrates, and therefore increase the clot fragmentation and lysis. This hypothesis has not been tested so far. The combination of rtPA, therapeutic ultrasound and NBO may be more efficacious than rtPA alone or its combination with ultrasound as acute stroke treatment modality, because each has different and probably additive mechanism of action. (c) 2005 Elsevier Ltd. All rights reserved.