Background and Purpose Obstructive sleep apnea (OSA) is associated with cerebral white-matter changes (WMC), but the underlying mechanisms are not completely understood. Our aim was to identify the cardiovascular autonomic characteristics during sleep that are associated with cerebral WMC in OSA patients. Methods We recruited subjects from our sleep-center database who underwent both polysomnography and brain MRI within a 1-year period. Sixty patients who had OSA with WMC (OSA+WMC), 44 patients who had OSA without WMC (OSA−WMC), and 31 control subjects who had neither OSA nor WMC were analyzed. Linear and nonlinear indices of heart-rate variability (HRV) were analyzed in each group according to different sleep stages and also over the entire sleeping period. Results Among the nonlinear HRV indices, the Poincaré ratio (SD12) during the entire sleep period was significantly increased in the OSA+WMC group, even after age adjustment. Meanwhile, detrended fluctuation analysis 1 during non-rapid-eye-movement sleep tended to be lowest in the OSA+WMC group. These indices were altered regardless of the presence of hypertension or diabetes. In the subgroup analysis of middle-aged OSA patients, approximate entropy during rapid-eye-movement sleep was significantly lower in OSA+WMC patients than in OSA−WMC patients. Overall, the nonlinear HRV indices suggest that sympathetic activity was higher in the OSA+WMC group than in the OSA−WMC and control groups. Conclusions Our findings suggest that dysregulation of HRV, especially overactivation of sympathetic tone, could be a pathophysiologic mechanism underlying the development of WMC in OSA patients.