The embryologic histogenesis of cartilage is not well characterized. While cranial cartilage is believed to be derived from pluripotential precursor cells of the neural crest, chondrocytes found elsewhere in the body are thought to be derived from mesoderm. As such, soft tissue tumors with cartilaginous differentiation may be related to neural crest or mesoderm. Peripherin is an intermediate filament encoded on chromosome 12, involved in growth and development of the peripheral nervous system. Peripherin is apparently expressed exclusively in cells derived from the neural crest and neural tube. A group of six soft tissue tumor types was selected because they are either of controversial differentiation or cytogenetically related to chromosome 12. A total of 41 cases was evaluated with antibodies against the intermediate filament peripherin. A panel of neural and neuroendocrine differentiation markers was used in selected cases. Three of five extraskeletal myxoid chondrosarcomas showed strong cytoplasmic reactivity with anti-peripherin. No peripherin expression was noted in any of eleven epithelioid sarcomas, eight liposarcomas, seven conventional chondrosarcomas, four neurothekeomas, three alveolar soft part sarcomas, or three clear cell sarcomas. The finding of peripherin expression in some extraskeletal myxoid chondrosarcomas may suggest the ability of some tumors to demonstrate both neural and chondroid differentiation.