Four cases of cutaneous S-100 negative granular cell tumor were described in 1991. Until now, only 3 cases of oral involvement have been documented in English literature. Two additional cases of oral S-100 negative granular cell tumor are described. Immunohistochemical markers were applied to exclude other lesions that may show the presence of granular cells. The clinical findings were correlated with the histopathological and immunohistochemical features to arrive at the appropriate diagnosis. S-100 negative granular cell tumors are erythematous polypoid masses commonly mistaken for granulation tissue or a pyogenic granuloma. Any part of the oral cavity may be affected. Histopathologically, the lesions consist of sheets, nests, and fascicles of granular cells that are S-100 negative. The granular cells are non-reactive to SMA, HMB45, Melan A, and CD163. The intracytoplasmic granules are diffusely and strongly positive to NKI/C3. The cell lineage of the S-100 negative granular cell tumor is obscure. Absence of staining with CD163 excludes a histiocytic lineage. Absence of staining with S-100 excludes a neural origin. Absence of staining with S-100 and key melanoma markers HMB45 and Melan A also excludes a melanocytic origin. In this context, positive reactivity with NKI/C3 is indicative of presence of intracytoplasmic lysosomal granules only. Greater awareness of this lesion in the oral cavity will result in better characterization of its biologic potential.