The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of manycancers, including colorectal cancer (CRC). DEPTOR is an mTOR inhibitor whose expression is negativelyregulated by mTOR. However, the role of DEPTOR in the development of CRC is not known. The aim of thisstudy was to investigate the expression of DEPTOR and mTORC1 activity (P-S6) in a subset of CRC patientsand determine their relation to tumor differentiation, invasion, nodal metastasis and disease-free survival. Here,Immunohistochemical expression of P-S6 (S235/236) and DEPTOR were evaluated in 1.5 mm tumor cores from90 CRC patients and in 90 samples of adjacent normal mucosa by tissue microarray. The expression of P-S6(S235/236) was upregulated in CRC, with the positive rate of P-S6 (S235/236) in CRC (63.3%) significantly higherthan that in control tissues (36.7%, 30%) (p<0.05). P-S6 (S235/236) also correlated with high tumor histologicgrade (p=0.002), and positive nodal metastasis (p=0.002). In contrast, the expression level of DEPTOR wascorrelated with low tumor histological grade (p=0.006), and negative nodal metastasis (p=0.001). Interestingly,P-S6 (S235/236) expression showed a significant negative association with the expression of DEPTOR in CRC(p=0.011, R= -0.279). However, upregulation of P-S6 (S235/236) (p=0.693) and downregulation of DEPTOR(p=0.331) in CRC were not significantly associated with overall survival. Thus, we conclude that expression ofDEPTOR negatively correlates with mTORC1 activity and tumor progression in CRC. DEPTOR is a potentialmarker for prognostic evaluation and a target for the treatment of CRC.