A great deal of attention has been given to epithelial differentiation in Ewing family of tumors (EFTs) in recent years, with studies showing variable keratin expression in 20% to 32% of cases. A 29-year-old man presented with a right-sided Horner syndrome suggesting a sympathetic chain related lesion. No radiologic evidence of a mass was appreciated initially. Several months later, he developed right vocal cord palsy and a large right-sided neck mass. An open biopsy demonstrated a high-grade malignant neoplasm with sheets of undifferentiated round cells infiltrating soft tissues and a large peripheral branch of the vagus nerve. Focally, the tumor abruptly produced keratinizing cells and frank squamous pearls. The tumor showed diffuse expression of CD99, high molecular weight keratin, p63, cytokeratin (CK) 5/6, AE1/AE3, CAM5.2, CK19, and focal CK14. It was negative for muscle-specific actin, desmin, MyoD1, MYF-4, S100, and CK7. Ultrastructurally, abundant cytoplasmic tonofilaments and well-formed desmosomes were demonstrated. Initial diagnosis was a metastatic squamous cell carcinoma of probable upper aerodigestive origin. Subsequently, the tumor was shown to harbor the t(11;22) involving EWSR1 and FLI-1 by reverse transcription-polymerase chain reaction, characteristic of EFT's, which was confirmed by dual color break apart fluorescence in-situ hybridization analysis. This tumor is related to, if not an example of the recently described "adamantinoma-like" EFT and demonstrates a potential diagnostic pitfall. It seems to be the first EFT to arise within, or in close proximity to the cervical sympathetic chain of ganglia. It is also the first EFT with complex epithelial differentiation arising outside the extremities and with diffuse expression of high molecular weight keratin and p63.