Purpose This cross-sectional study compared the peripapillary vessel density and retinal nerve fiber layer (RNFL) thickness in patients with exfoliation syndrome (XFS) and healthy controls for evaluation of the early structural and vascular alterations in XFS. Methods One eye was included from 75 patients with XFS and 54 healthy controls. The patients with XFS were matched the controls for age, intraocular pressure and axial length. The vascular density of the radial peripapillary capillaries (RPCs) and the peripapillary RNFL thickness were evaluated with optical coherence tomography angiography. Results The mean peripapillary RNFL thicknesses of the groups were similar in all sectors (p > 0.05 for all). However, eyes with XFS demonstrated lower mean peripapillary vessel densities in all areas (p < 0.05 for all) except for the nasal sector (p = 0.68) compared to the controls. The gradual age correlated decline in the peripapillary RNFL thickness and the RPC vessel density observed in the healthy eyes was absent in XFS (r = - 0.14 p = 0.65 and r = - 0.23 p = 0.05). Conclusions Alterations in the peripapillary vascular density despite a preserved RNFL thickness in XFS supports the hypothesis that vascular alterations may precede structural alterations and have an important role in the pathogenesis of XFS. XFS may have different effects on the microvasculature of different peripapillary areas, with the nasal sector being mostly preserved.