The brain is protected from the entry of foreign substances by blood-brain barrier (BBB), but becomes a barrier while chemotherapy is needed for the brain diseases. Ultrasound with microbubbles (MBs) has been shown to noninvasively increase the permeability of the BBB in the normal tissue and brain tumor. The real mechanism for disruption is still unknown. Hemorrhage was usually found in the sonicated region of the brain. Thus, treatment safety is the primary concern when considering clinical application of BBB disruption induced by ultrasound in the presence of MBs. Here we investigate the effects of ultrasound on the permeability of BBB whether the MBs were administered. The data reveals that Evans blue (EB) accumulation was highest in the brain after sonication with MBs. However, the permeability of BBB also can be significantly increased by ultrasound alone. These results demonstrated that noninvasive disruption of BBB by ultrasound alone with no damage is possible.