A-50-year-old Hispanic man presented to the dermatology clinic with a 0.6-cm eroded, erythematous, scaly plaque on the left side of his neck. On shave biopsy, the lesion was composed of intra-epidermal and invasive dermal cells characterized by a signet-ring appearance. One area suggestive of typical squamous cell carcinoma prompted the inclusion of that entity in the differential diagnosis. Mucicarmine stains were negative, while the extra-vacuolar cytoplasm focally reacted with periodic acid-Schiff staining, the positive reaction for which was abolished by diastase, consistent with glycogen. Malignant cells expressed keratins by reacting to antibodies, Mak6, AE1/AE3, Ker 903, and CAM5.2. Additionally, weak reactivity occurred with antibodies to CEA and EMA. Tumor cells did not express S-100, HM-B45, Leu M1, or actin. By ultrastructural examination, the large vacuoles corresponded to markedly dilated endoplasmic reticulum. A diagnosis of signet-ring squamous cell carcinoma, a rare form of cutaneous squamous cell carcinoma which has been described in only one case report in the last 10 years, was made. Immunohistochemical staining provided information useful in differentiating this lesion from other clear cell and signet-ring cell tumors which involve the skin.