Retinal Vasculopathy with Cerebral Leukodystrophy and Systemic manifestations (RVCL-S) is a monogenic cerebral small vessel disorder attributable to a mutation in TREX1, characterized by progressive microvascular pathology and associated with cognitive and behavioral changes. In the Netherlands, only three affected families have been identified, limiting knowledge on cerebral involvement and longitudinal disease progression. Enlarged perivascular spaces (ePVS) are considered imaging markers of small vessel and glymphatic dysfunction and may reflect early microvascular brain changes. This study examined whether baseline regional ePVS burden is increased in RVCL-S compared with healthy controls, whether ePVS burden relates to global cognitive functioning at baseline, and whether longitudinal changes in ePVS are associated with cognitive decline in RVCL-S patients. Genetically confirmed RVCL-S patients and healthy controls underwent standardized 3T MRI and neuropsychological assessment at baseline and annual follow-up. ePVS were visually rated in the basal ganglia (BG) and centrum semiovale (CSO). Cross-sectional linear regression and longitudinal mixed-effects models were applied. RVCL-S patients showed higher BG ePVS burden at baseline compared with controls, whereas no differences were observed in the CSO. This group effect attenuated after adjustment for white matter hyperintensities. No significant cross-sectional or longitudinal associations were found between regional ePVS burden and global or domain-specific cognitive functioning. These findings suggest that although BG ePVS are modestly increased in RVCL-S at baseline, they are not independently associated with cognitive decline within the current follow-up period.