To date, neuropsychiatric profiles in Sjögren’s syndrome patients are not explained by the immunological profile or clinical symptoms. Consequently, there is a lack of biomarkers potentially characterizing such profiles for this rare autoimmune disease. Our goal was to investigate the potential of MRI-based features to objectively explain fatigue, depression and cognitive complaints in twenty-nine patients with primary Sjögren’s syndrome. Specifically, we explored features from automated brain morphometry and brain lesion segmentation as potential imaging biomarkers. Z-score differences in certain brain structures (thalamus, corpus callosum, ventricles, and insula) were found, suggesting an association between MRI-based biomarkers and patient’s neuropsychiatric profiles.