OBJECTIVE: To investigate whether the expression of cryptochrome (CRY1 and CRY2) proteins could be a novel prognostic marker to predict the overall outcome of patients with hepatocellular carcinoma (HCC). Disruption of the circadian homeostasis is closely correlated with carcinogenesis. The CRY1 and CRY2 genes act as negative regulators in the circadian period through the transcription/translation feedback loop. STUDY DESIGN: Immunohistochemical staining in this study evaluated the expression levels of CRY1 and CRY2 proteins. RESULTS: The immunohistochemical results showed a close correlation of the high expression of CRY1 protein with tumor differentiation, TNM stage, lymph node status, and alpha-fetoprotein. Also, the high expression of CRY2 protein was correlated with tumor differentiation, TNM stage, and portal invasion. The Kaplan-Meier curve analysis showed that the high expression of CRY1 and CRY2 proteins was significantly correlated with the overall survival of patients with HCC. The Cox proportional hazard regression model analysis showed that the expression of CRY1 and CRY2 was an independent prognostic factor for overall survival in patients with postoperative HCC. CONCLUSION: The present findings indicated that the expression of CRY1 and CRY2 was a potential biomarker for the prognosis and therapy in patients with HCC.