The purpose of this study was to examine the reproducibility of biopsy grades at various tissue depths in Sjögren’s syndrome. The biopsy grades of 38 minor salivary gland biopsies were examined at 6 μm, 50 μm, 100 μm, 150 μm, 200 μm, and 250 μm tissue depths. Tissue sections were stained with routine hematoxylin and eosin, graded I–IV, and compared with the initial “baseline” biopsy grade. The majority of the biopsies showed a wide range of grade variability at all depths. No tissue depth was consistently reproducible for any grade (P0.41, 0.64, 0.91, and 0.20, respectively). The difference between baseline grades and grades of deeper sections was sufficient to impact the diagnosis of Sjögren’s syndrome in approximately 60% of the biopsies (P<0.001). The overall result of this study suggests that examination of multiple sections of minor salivary gland biopsies is advisable to improve the reliability of the grade when evaluating Sjögren’s syndrome.