There have been paradoxical findings regarding the expression of DEP domain-containing mTOR-interacting protein (DEPTOR) and its role in predicting prognosis in esophageal squamous cell carcinoma (ESCC). Here we show that DEPTOR expression was significantly increased in tumor tissues and predicted good survival in early stage ESCC patients but not in advanced stage patients. In vitro, our studies showed that ESCC cell lines could be classified into relatively high and low DEPTOR-expressing subgroups according to esophageal squamous epithelial cell line Het-1A.In our study, different levels of DEPTOR expression absolutely determined the response to chemotherapy. In relatively low-expressing cell lines, DEPTOR increased chemotherapy sensitivity via deactivation of the AKT pathway. In relatively high-expressing cell lines, DEPTOR increased cell survival and chemoresistance by strong feedback activation of the IRS1-PI3K-AKT-survivin pathway that occurred after downregulation of ribosomal protein S6 kinase (S6K). Collectively, our findings highlight the dichotomous nature of DEPTOR functions in modulating chemotherapy sensitivity in different ESCC cells.