Our purpose was to investigate the role of SOX9, a novel downstream molecule of β-catenin, in colorectal cancer. Expression of SOX9 and β-catenin was detected by immunostaining, quantitative real-time reverse transcription–polymerase chain reaction (Q-PCR), and Western blot in colorectal cancer. The correlation between SOX9 or β-catenin expression and clinicopathologic parameters was also analyzed. Immunostaining, Q-PCR, and Western blot consistently confirmed SOX9 up-regulation in colorectal cancer compared with normal mucosa (P < .05). Immunostaining showed more SOX9+ cells in the lower zone of colonic crypts than in the upper zone (P < .05). Cancers with strong SOX9 immunostaining were significantly associated with a lower 5-year overall survival (40% [17/43] vs low expression, 69% [66/95]; P <.01). The Cox proportional hazards model showed that strong SOX9 expression was an independent adverse prognosticator in colorectal cancer (P < .05). The detection of SOX9 expression might contribute to predicting clinical outcomes for patients with colorectal cancer.