Although the distribution of [99mTc]hexamethylpropyleneamine oxime (HM-PAO) in the brain is said to be in a flow-related manner without temporal change, we present cases with leakage of [99mTc]HM-PAO (filling out phenomenon) in the delayed image of brain single photon emission computed tomography (SPECT) and clarify its clinical significance. The filling out phenomenon was observed in seven out of 21 cases of cerebrovascular disease and four cases of arteriovenous malformation. The leakage of [99mTc]HM-PAO was also confirmed by visual and semiquantitative analysis. In the pharmacokinetics of [99mTc]HM-PAO in the blood, the percent dose of plasma fraction at 4 hr was reduced to 54% of activity at 30 min. The percent dose of brain blood could be predicted as 3.36%/1 at 30 min and 2.35%/1 at 4 hr after correction with the hematocrit of the brain. The filling out phenomenon of [99mTc]HM-PAO was attributed to a significant reduction of blood activity of [99mTc]HM-PAO in the plasma. Since the initial image might mask reduced rCBF with an increase of rCBV, the late image would have an advantage in accurately evaluating rCBF from the clearance of [99mTc] HM-PAO bound to the plasma. Therefore, the filling out phenomenon of [99mTc]HM-PAO in late images of brain SPECT could show the area of mild cerebral ischemia accompanying cerebral vascular reserve.