The purpose of this study was to evaluate retinal thickness in different Xeroderma Pigmentosum (XP) complementation groups using spectral-domain optical coherence tomography (SD-OCT). This was a cross-sectional pilot study of 40 patients with XP. All patients had healthy-looking retinae and optic nerves on slit lamp biomicroscopy, and subtle or no neurological deficits. Patients were divided into two groups based on the known tendency for neurodegeneration associated with certain XP complementation groups. A third control group was obtained from a normative database. Using SD-OCT, we compared peripapillary retinal nerve fibre layer (pRNFL) and macular thickness between the groups. XP patients with a known tendency for neurodegeneration were found to have a statistically significant reduction in both pRNFL (p < 0.01) and macular thickness (p < 0.001) compared with healthy controls. In contrast, there was no statistically significant difference between pRNFL and macular thickness in XP patients not expected to develop neurodegeneration compared to the same control group. When both XP groups were compared, a statistically significant reduction in total pRNFL (p = 0.02) and macular thickness (p = 0.002) was found in XP patients predisposed to neurodegeneration. Our results suggest that pRNFL and macular thickness are reduced in XP patients with a known tendency for neurodegeneration, even before any marked neurological deficits become manifest. These findings demonstrate the potential role of retinal thickness as an anatomic biomarker and prognostic indicator for XP neurodegeneration.