Ubiquitin-specific protease 14, also known as the 60 kDa subunit of tRNA-guanine transglycosylase (USP14/TGT60kD), belongs to the ubiquitin-specific processing protease (UBP) family. USP14/TGT60kD expression in leukemic and colorectal cancer cell lines, and the suppression of such an expression after the induction of cell differentiation have been reported. In the present study, we attempted to clarify whether USP14/TGT60kD overexpression affects the clinicopathological features of colorectal cancer. Immunohistochemically, USP14/TGT60kD was absent or weakly localized in the cytoplasm of normal colorectal epithelial cells. In 18 of 99 (18.2%) colorectal cancer patients, USP14/TGT60kD was strongly detected in the cytoplasm of cancer cells. USP14/TGT60kD expression correlated with pathological stage (P= 0.03), and lymph node (P= 0.03) and liver (P= 0.03) metastases. Furthermore, the percentage of patients strongly positive for USP14/TGT60kD expression increased with pathological stage. The overall survival rate was worse in patients with a high USP14/TGT60kD expression level than in those with a low USP14/TGT60kD expression level. Our results suggest that USP14/TGT60kD also controls the fate of proteins that regulate tumor invasion and metastasis.