Neurothekeoma is a term introduced by Gallager and Helwig describing a superficial tumor of purported nerve sheath derivation, with cellular and myxoid types. Recently, it has been suggested that the cellular type does not have nerve sheath differentiation. This subtype represents an uncommon neoplasm and sometimes can be problematic to diagnose because it can be easily mistaken for melanoma. We studied the immunohistochemical features of 31 cases of cellular neurothekeomas to evaluate their immunoprofile. Immunohistochemical studies were performed in all 31 cases with formalin-fixed paraffin-embedded tissue sections with antibodies against S100 protein, S100A6, and melanoma antigen recognized by T-cells (MART-1). In addition, 8 cases were evaluated for HMB-45 antigen, keratin (with a pankeratin cocktail), epithelial membrane (EMA), and smooth muscle antigen (SMA). The lesions were from 8 men and 23 women aged 6-64 years (mean 35 years). Four tumors were located on the nose; 4 scalp; 4 finger; 3 thigh; 2 shoulder; 2 wrist; 2 hand; and 1 each on pelvis, cheek, toe, chest, eyebrow, forearm, penis, axilla, mouth, and leg. All tumors were positive for S100A6 (100%) and negative for cytokeratin, HMB-45 antigen, MART-1, and EMA (100%); 29 cases were negative for S100 protein (93.5%; the 2 positive cases had only scattered cells labeled), and only 2 cases were focally positive for SMA (7.5%). Therefore, the combination of strong immunoreactivity for S100A6, in nested dermal spindle cell proliferations, and lack of S100 protein or keratin, supports a diagnosis of cellular neurothekeoma.