In the present study, we examined the expression pattern of ODC in ESCC cell lines and tissues. Then we investigated the functions of ODC in ESCC development by using shRNA and an irreversible inhibitor of ODC, difluoromethylornithine (DFMO). Our data showed that ODC expression was up-regulated in human ESCC tissues and ESCC progression could be attenuated by suppressing ODC activity, indicating that ODC might be a promising target for ESCC therapy.