Purpose: To evaluate the changes in cornea in Sjögren’s syndrome (SS) with a novel confocal microscopy device. Methods: Twenty-three right eyes of patients with SS (23 women; mean age, 65.4 ± 11.4 years) and 13 right eyes of 13 age- and sex-matched control subjects (13 women; mean age, 68.8 ± 9.8 years) were studied. Furthermore, eight right eyes of patients with SS (8 women; mean age, 66.9 ± 9.6 years) were studied to evaluate the corneal microscopic alterations after the treatment with topical 3% diquafosol sodium eye drops. All cases had tear quantity, tear breakup time (BUT), ocular surface staining measurements, and corneal in vivo laser-scanning confocal microscopy examinations. The density and area of corneal epithelial cells (superficial, wing, and basal), density of corneal stromal cells (anterior, intermediate, and posterior), density and area of corneal endothelial cells, density and morphology of corneal sub-basal nerve plexus, density of corneal sub-basal inflammatory cells were also assessed. Results: The tear quantity, stability, and vital staining scores were significantly worse in patients with SS than in control subjects (p
< 0.0001). Corneal superficial epithelial cell density was significantly lower in SS compared with control subjects (p
< 0.0001). Corneal superficial epithelial cell area was significantly larger in SS compared with control subjects (p
= 0.007). Corneal sub-basal nerve fiber density was lower in SS compared with control subjects (p
< 0.0001). Morphological abnormality of nerve fibers was observed in SS patients. Corneal sub-basal inflammatory cell density was significantly higher in SS patients compared with control subjects (p
< 0.0001). Furthermore, the mean corneal superficial epithelial cell density and area, inflammatory cell density, corneal sub-basal nerve fiber density, and morphological abnormality of nerve fibers, were improved with topical 3% diquafosol sodium treatment in the dry eye patients with SS (p
< 0.05). Conclusions: The diagnostic modality using in vivo laser-scanning confocal microscopy was a useful method for the evaluation of the corneal cell density and area, nerve fiber density and morphology, and inflammatory cell density in patients with SS and also a useful tool in the assessment of treatment effect with topical 3% diquafosol sodium in the SS patients.