OBJECTIVE: The aim of this study was to explore the association between cathepsin K and the clinical characteristics of skull base chordoma (SBC). METHODS: This study included 58 paraffin-embedded samples and 85 frozen samples of 94 patients. All clinical data corresponding to these patients were available. Immunohistochemical staining and quantitative real-time polymerase chain reaction were performed. Positive rate of immunohistochemical staining slices and delta cycle threshold value of quantitative real-time polymerase chain reaction represented the cathepsin K expression level in protein and gene level separately. RESULTS: In protein level, expression level (EL) of invasive tumors was increased compared with noninvasive tumors (P = 0.006), EL of tumors with dura erosion was increased compared with tumors without dura erosion (P = 0.001). Tumors with septa exhibited increased EL compared with tumors without septa (P = 0.001). Tumors with lobulation exhibited increased EL compared with tumors without lobulation (P = 0.000). Higher EL of cathepsin K was associated with reduced progression-free survival (PFS) (P = 0.015). In gene level, tumors with septa showed higher EL than tumors without septa (P = 0.015), and tumors with lobulation showed higher EL than tumors without lobulation (P = 0.049). Cathepsin K EL was an independent risk factor for reduced PFS, and an increased level of cathepsin K in SBC was associated with reduced PFS (P = 0.042). CONCLUSIONS: Increased cathepsin K expression in SBC was associated with tumor invasion and reduced PFS. The cathepsin K level in SBC also was associated with tumor stage, tumor lobulation, and septa.