Distinction of enchondroma versus intramedullary chondrosarcoma affecting the appendicular skeleton (proximal to the metacarpals and metatarsals) is a frequent diagnostic dilemma. The authors studied a large series of patients with these lesions (92 with enchondromas, 95 with chondrosarcomas) using statistical assessment of both clinical parameters and numerous radiologic manifestations on images from multiple modalities to identify differentiating features. Multiple clinical and imaging parameters demonstrated statistically significant differences between enchondroma and chondrosarcoma, particularly pain related to the lesion, deep endosteal scalloping (greater than two-thirds of cortical thickness), cortical destruction and soft-tissue mass (at computed tomography or magnetic resonance imaging), periosteal reaction (at radiography), and marked uptake of radionuclide (greater than the anterior iliac crest) at bone scintigraphy. All of these features strongly suggested the diagnosis of chondrosarcoma. These criteria allow distinction of appendicular enchondroma and chondrosarcoma in at least 90% of cases.