Impaired sleep-related activation of the cerebral waste-clearance system might be related with the brain aging process. We hypothesized that cerebral blood-flow pattern changes during sleep might reflect the activation of the cerebral waste-clearance system and investigated its association with the cerebral white-matter hyperintensity (WMH) volume. Fifty healthy volunteers were prospectively recruited. In addition to the baseline transcranial Doppler parameters, the mean flow velocity (MFV) of the middle cerebral artery was monitored during waking and short-term non-REM sleep. Spectral density analysis was performed to analyze the periodic MFV variation patterns. For the aged subgroup (>50 years, n = 25), the WMH volumes in the total, subcortical, and periventricular regions were measured. The MFV periodic pattern during sleep was substantially augmented over that in the waking status. Spectral density analysis of MFV showed a noticeable peak in the very-low-frequency (VLF) band during sleep status (sleep/waking ratio 2.87 ± 2.71, P < 0.001). In linear regression analysis in the aged subgroup, the sleep/waking ratio of the VLF peak was inversely associated with total (P = 0.013) and subcortical (P = 0.020) WMH volumes. Sleep-related amplification of the cerebral flow-velocity periodicity might reflect the activation of cerebral waste clearance system during sleep, and be related to the pathogenesis of cerebral WMH.