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Melanoma is the most common malignant oral tumor in dogs. It frequently presents a diagnostic challenge as many melanomas lack or contain scant melanin and may have a variable microscopic phenotype. Previous studies evaluating immunohistochemical markers for diagnosing melanoma have shown limited sensitivity and/or specificity for S-100, PNL2, melan A, TRP-1, TRP-2, and HMB-45. Sry-related HMG-box gene 10 (SOX-10) is a transcription factor associated with melanocytic, peripheral neural crest, and peripheral nervous system development. In humans, SOX-10 expression has been demonstrated in melanoma, breast carcinoma, glioma, and schwannoma, but has only recently been explored in veterinary species. In this study, 198 tumors comprised of 147 melanocytic neoplasms and 51 non-melanocytic neoplasms were evaluated by immunohistochemistry using a tissue microarray for SOX-10, PNL2, melan A, TRP-1, and TRP-2 expressions. The SOX-10 had the highest diagnostic sensitivity (96.7%) in melanomas. In addition, SOX-10 had the highest percentage (91.5%; 130/142) of melanomas label at least 75% of neoplastic cells. Of the 51 selected non-melanocytic tumors examined, SOX-10 labeling was observed in mammary carcinomas (6/6), gliomas (4/4), and oral soft tissue sarcomas (4/18). Of the 41 non-melanocytic oral neoplasms evaluated, SOX-10 had a specificity of 92.7%. Therefore, SOX-10 represents a useful immunohistochemical screening marker for the diagnosis of canine melanoma given its extremely high sensitivity and robust labeling intensity. The SOX-10 may have utility in diagnosing some non-melanocytic neoplasms in the dog, although this requires further investigation. [ABSTRACT FROM AUTHOR]