Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare thyroid tumor of unknown histogenesis with a high female predilection. It shows dual squamous and mucinous differentiation demonstrated by diffuse p63 or p40 expression and appreciable mucocytes, respectively. Thyroid transcription factor 1 (TTF1) is expressed in up to 50% of tumors while paired-box 8 (PAX8) and thyroglobulin are usually negative. No specific molecular signature has been described as a tumor driver. In this article, we present a 47-year-old man with an SMECE with peculiar histological and immunohistochemical features, including rare mucocytes highlighted by Alcian blue periodic acid—Schiff stain and diffuse cytokeratin 5/6 (CK5/6) expression while p40 was almost absent. TTF1 and PAX8 were weakly to moderately expressed. Molecular analysis, including next-generation sequencing and a solid fusion tumor assay, identified no driver alterations. A methylome analysis was inconclusive for a putative cell of origin.