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An unusual case of synchronous squamous cell carcinoma and leiomyosarcoma of the oral cavity is reported in a patient without any identified environmental risk or predisposing factors. The invasive squamous cell carcinoma involved the tongue, whereas the leiomyosarcoma was located in the soft palate. No immunostaining was found for human papillomavirus or Epstein-Barr virus, and in situ hybridization showed negativity for human papillomavirus DNA within the tumor cells. Alterations of bcl-2, c-erb-b2 and Rb oncoproteins were not found immunohistochemically. Overexpression of p53 was detected by immunohistochemistry in both tumors, but p53 gene mutations were not found by polymerase chain reaction. Neither loss of heterozygosity of p53 nor microsatellite instability was detected in this patient. The smooth muscle nature of the leiomyosarcoma was confirmed by immunohistochemical methods. To our knowledge, synchronous smooth muscle and epithelial oral tumors have not previously been reported.