AIM: To investigate the molecular mechanism through which DKK1 is transcriptionally regulated in HCC (hepatocellular carcinoma) cells. METHODS: Real time PCR was used to explore whether EGFR was involved in regulating DCLK1 mRNA expression in HCC cells; Western blot assay was used to examine whether EGFR-mediated the up-regulation of DCLK1 protein in HCC cells; Immunohistochemical (IHC) analyses were used to examine the protein expression of EGFR and DCLK1 in 39 human HCC tumor specimens. RESULTS: EGF promoted the expression of DCLK1 mRNA and protein in HepG2 and Huh-7 cells (P<0.05, P<0.01), while knockdown of EGFR with two specific siRNA could reverse EGF-induced the up-regulation of DCLK1 mRNA and protein (P<0.01). IHC analyses revealed that the amount of EGFR correlated significantly with that of DCLK1 (r=0.669 6). CONCLUSION: EGFR promoted DCLK1 transcription in HCC.