Somatic mutations of the epidermal growth factor receptor (EGFR) gene may predict the sensitivity of non-small cell lung cancers to gefitinib. In our previous study, we identified somatic mutations in the tyrosine kinase domain of the EGFR gene in 12.1% of colon cancer cases. Herein, we focus on whether the mutations are associated with the sensitivity of colon cancer to gefitinib. The E749K mutation in exon 19 and E762G and A767T mutations in exon 20 were introduced into the full-length EGFR coding sequence in a pBKCMV-hEGFR vector by site-directed mutagenesis and transfected into LS174T cells. The sensitivity to gefitinib was compared between the transfected LS174T and the parental cells by a cytotoxic assay. The LS174T cells with E749K were significantly (p<0.05) more responsive to gefitinib than the parental cells. On the other hand, LS174T cells with E762G or A767T were significantly (p<0.05) more resistant than the parental cells. In conclusion, detection of somatic mutations in the epidermal growth factor receptor may play an important role in predicting sensitivity to gefitinib in colon cancer.