The Ewing sarcoma breakpoint region 1 (EWSR1) is translocated in many sarcomas. Recently, its rearrangement has been described in salivary gland hyalinizing clear cell carcinomas (HCCCs) and in a subset of soft tissue myoepitheliomas. This study examines the presence of the EWSR1 rearrangement in a variety of salivary gland lesions including classic myoepitheliomas and HCCCs. Using a tissue microarray and whole-mount sections, fluorescence in situ hybridization (FISH) was performed on a variety of salivary gland lesions including HCCCs. The EWSR1 rearrangement was detected in 87% of HCCCs (13 of 15); all other salivary gland lesions including classic myoepitheliomas had intact EWSR1. Patients with HCCCs with rearranged EWSR1 included 1 man, 10 women, and 2 of unknown sex. Ages ranged from 35 to 83 years; the tumor size ranged from 0.8 to 5.5 cm, and the involved locations included: palate (2), base of the tongue (2), mandible (2), submandibular gland (2), lip (1), floor of the mouth (1), sublingual gland (1), inner cheek (1), and nasopharynx (1). All HCCCs were composed of sheets and nests of monotonous cells with clear cytoplasm within a hyalinized stroma. All tested cases were immunoreactive with antibodies to p63 and were nonreactive with antibodies to more conventional myoepithelial antigens (e.g., smooth muscle actin and S100 protein). These findings show that the EWSR1 rearrangement is almost a defining feature of HCCCs and also confirm that classic salivary gland myoepitheliomas are distinct from these tumors and do not share a pathogenetic relationship with their soft tissue counterparts.