Ciliobrevin A, also known as HPI-4 and Hedgehog Pathway Inhibitor 4, is a Hedgehog pathway inhibitor. Treatment with HH pathway inhibitor-4 (HPI-4) could significantly decrease human chondrosarcoma cell proliferation, invasion and migration ability. Furthermore, HPI-4 could distinctly disturb HH pathway-mediated ciliogenesis and suppress primary cilia-related protein intraflagellar transport protein IFT88 expression. HH downstream effect molecular GLI2 was restrained to block parathyroid hormone-related protein and affect MAPK/ERK-regulated matrix metalloproteinases (MMP2 and MMP9). d HPI-4 could be a new therapeutic option specific to chondrosarcoma expressing elevated levels of HH pathway.