Objective: To investigate the expressions of Numb and vascular endothelial growth factor (VEGF) in primary hepatocellular carcinoma (HCC), and the clinical significance. Methods: The Numb and VEGF expressions in the surgical specimens of HCC tissue along with tumor adjacent tissues from 60 HCC patients, and normal liver tissues from 27 cases with liver injury or hepatic hemangioma were determined by immunohistochemical staining. The relations of Numb and VEGF expressions with the clinicopathologic factors and prognosis of the HCC patients were analyzed. Results: Compared with normal hepatic tissue and tumor adjacent tissue, the positive Numb expression rate was significantly decreased, while the positive VEGF expression was significantly increased in HCC tissue (both P<0.05), further, there was a negative relation between Numb and VEGF expression in HCC tissue (r=–0.5248, P=0.01). Both Numb and VEGF expressions were significantly associated with TNM stage, and Edmondson grade, and the presence or absence of portal cancer embolus and tumor capsule (all P<0.05). The overall survival period in patients with negative Numb expression was significantly shorter than in those with positive Numb expression, but the finding for VEGF expression was the opposite of that (both P<0.05). Conclusion: Numb expression is decreased and VEGF expression is increased in HCC tissue, and waxing and waning between them may closely relate to the invasiveness and poor prognosis of HCC.