Background <p>Cytoplasmic granularity is a distinctive histomorphologic feature observed in several oral lesions and is commonly attributed to the accumulation of lysosomes or other intracellular organelles. Granular cell tumor (GCT) and congenital epulis (CE) are two such lesions that exhibit strikingly similar microscopic appearances on routine hematoxylin and eosin staining, despite differing in clinical presentation, biological behavior, and histogenesis. This histochemical and immunohistochemical note aims to highlight the nature and diagnostic significance of cytoplasmic granules in these two entities.</p> Results <p>Periodic acid–Schiff (PAS) staining shows variable positivity in both lesions and therefore provides limited discriminatory value. In contrast, Luxol fast blue (LFB) reliably demonstrates myelin-rich cytoplasmic granules in GCT, while CE remains negative. Immunohistochemically, GCT consistently expresses S-100 protein and CD68, supporting Schwann cell differentiation with lysosome-rich granules. CE, however, lacks S-100 expression and demonstrates absent or weak CD68 staining, favoring a non-neural, likely mesenchymal or hamartomatous origin.</p> Conclusion <p>The combined use of histochemical stains and immunohistochemistry provides important diagnostic clues in differentiating GCT from CE. Recognition of the distinct staining profiles and immunophenotype of these lesions, in conjunction with morphologic assessment, can help avoid diagnostic ambiguity and ensure accurate diagnosis.</p>