The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial tumors and plays an important role in the tumorigenesis of these tumors. Inhibitors of EGFR reduce the proliferation rate of cancers and are promising therapeutic agents of cancers. Recently, two studies have identified somatic mutations in the exons 18-21 of EGFR that were strongly correlated with robust clinical response to gefitinib treatment in patients with non-small cell lung cancer. To investigate whether EGFR mutation is involved in the tumorigenesis of hepatocellular carcinoma (HCC), we performed direct sequencing of exons 18-21 on 89 HCCs. No mutations causing amino acid changes or deletions were identified. The results indicate mutation of the kinase domain of EGFR does not play a significant role in the tumorigenesis of HCC and gefitinib is unlikely to be used as single-drug therapy for HCC.