Benign nerve sheath tumors include neurofibromas, schwannomas, and perineuriomas. In recent years, nerve sheath tumors showing discrete areas of more than one histologic type have been described. We have recently recognized tumors showing hybrid features of schwannoma and soft tissue perineurioma. To characterize the clinicopathologic and immunohistochemical features of these lesions, 42 cases received between 1994 and 2008 were retrieved from authors' consult and surgical pathology files. Clinical details and follow-up were obtained from referring pathologists. Hematoxylin and eosin-stained sections were reexamined, and immunohistochemistry was performed. On 10 cases, double labeling with epithelial membrane antigen (EMA) and S100 protein was performed. Twenty-two patients were female and 20 were male (mean age, 38 y; range: 2 to 85; 71% second to fifth decades). Most patients presented with a solitary painless nodule. The tumors arose in a wide distribution: 19 lower limb, 12 upper limb, 6 head and neck, 4 trunk, and 1 colon. None of the patients showed signs of neurofibromatosis. Tumor size ranged from 0.7 to 17.5 cm (mean, 3 cm). Most tumors involved superficial subcutis (11 also dermis); only 3 were intramuscular. Histologically, the tumors were usually well circumscribed but unencapsulated, and composed of spindle cells with plump, tapering nuclei, and palely eosinophilic cytoplasm with indistinct cell borders, arranged in a storiform, whorled, and/or lamellar architecture. Only 1 tumor showed infiltrative margins. One tumor showed a plexiform growth pattern. Antoni A and B zonation and hyaline vessels were absent. Six tumors showed focally myxoid stroma and 11 contained scattered cells with degenerative nuclear atypia. Mitoses ranged from 0 to 4 per 30 high power fields; 32 tumors had no mitoses. All tumors showed staining for S100 protein and EMA; 98% were positive for CD34, 84% for GFAP, and 80% for claudin-1. Fourteen tumors contained rare neurofilament protein-positive axons. Double staining for EMA and S100 protein revealed parallel layers of alternating S100 and EMA-positive cells with no coexpression of antigens by the same cells. Most tumors were composed of approximately 60% to 70% of Schwann cells and 30% to 40% of perineurial cells. After a mean follow-up of 24 months (range, 6 to 60 mo), 1 tumor recurred locally, after incomplete excision. Benign nerve sheath tumors showing predominantly schwannian cytomorphology and perineurioma-like architecture are composed of an admixture of both cell types. These tumors usually arise in the dermis and subcutis and occur over a wide age range and anatomic distribution. Degenerative nuclear atypia (akin to that seen in ancient schwannoma and atypical neurofibroma) is relatively common. Hybrid schwannoma/perineuriomas have no evident association with neurofibromatosis and rarely recur. The pathogenetic basis of the dual pattern of differentiation in these lesions remains poorly understood at this time.