Insulin‐like growth factor II mRNA‐binding protein 3 (IMP3) is an RNA‐binding protein expressed in embryonic tissues and multiple cancers. To investigate the role of IMP3 in hepatocellular carcinoma (HCC), its protein expression in the surgically resected unifocal tumors of 377 HCC patients (296 men and 81 women) with ages ranging from 7 to 88 years (mean, 55.49 years) was analyzed by immunohistochemistry. IMP3 was expressed in 255 (67.6%) of 377 resected unifocal primary HCCs. IMP3 protein was predominantly expressed in tumor border and invasive front, and it was more abundant in the satellite nodules and tumor thrombi than in the main tumors. The expression correlated with high α‐fetoprotein (>200 ng/mL, P < 1 × 10⁻⁷), larger tumor size (>5 cm, P = 0.006), high tumor grade (P < 1 × 10⁻⁷), and high tumor stage with vascular invasion and various degrees of intrahepatic metastasis (P < 1 × 10⁻⁷). IMP3 expression predicted early tumor recurrence (P < 1 × 10⁻⁷) and was a strong indicator of poor prognosis (P < 0.0001). Depletion of IMP3 with RNA interference in HCC cell line HA22T caused a decrease in cell motility, invasion, and transendothelial migration. Microarray analysis revealed that IMP3 depletion was associated with downregulation of multiple genes involved in tumor invasion. Conclusion: Our results indicate that IMP3 plays an important role in tumor invasion and metastasis and is a strong prognostic factor for patients with HCC. (HEPATOLOGY 2008.)