Induction of differentiation and apoptosis in cancer cells by ligands of PPARγ is a novel therapeutic approach to malignant tumors. Chondrosarcoma (malignant cartilage tumor) and OUMS‐27 cells (cell line established from grade III human chondrosarcoma) express PPARγ. PPARγ ligands inhibited cell proliferation in a dose‐dependent manner, and induced apoptosis of OUMS‐27. The higher‐grade chondrosarcoma expressed a higher amount of antiapoptotic Bcl‐xL in vivo. The treatment of OUMS‐27 by 15d‐PGJ2, the most potent endogenous ligand for PPARγ, downregulated expression of Bcl‐xL and induced transient upregulation of proapoptotic Bax, which could accelerate cytochrome c release from mitochondria to the cytosol, followed by induction of caspase‐dependent apoptosis. 15d‐PGJ2 induced the expression of CDK inhibitor p21 protein in human chondrosarcoma cells, which appears to be involved in the mechanism of inhibition of cell proliferation. These findings suggest that targeted therapy with PPARγ ligands could be a novel strategy against chondrosarcoma.