The distinction between chondrosarcoma and enchondroma is difficult, and no reliable immunohistochemical or molecular methods are available. Differentiation is important because the therapeutic consequences range from radiologic followup to radical operation. We studied 17 chondrosarcomas (12 grade 1) and compared them with 14 enchondromas immunohistochemically by using the monoclonal antibodies Ki-MCM6 (minichromosome maintenance protein 6), Ki-S5 (Ki-67), and Ki-S2 (repp86), in addition to the established clinical criteria. In comparison with the other markers, Ki-MCM6 proved more effective at identifying proliferative activity in grade 1 chondrosarcomas. The MCM6 labeling index correlated with tumor grade and was significantly increased in grade 1 chondrosarcomas compared with enchondromas. The 5 cases of progressive chondrosarcoma also had a significantly higher MCM6 labeling index than the nonprogressive cases. Furthermore, by means of the MCM6 labeling index, many cases of progressive disease were recognized among those of uncertain malignant potential, justifying their classification as low-grade chondrosarcomas.