Background: Ubiquitin-specific proteases (USPs) play an important role in fundamental cellular processes. Among these, USP10 is known for its association with tumor development and progression of multiple cancers. Here, we found a potential link between USP10 and p14ARF in colorectal cancer.Methods: USP10 and p14ARF protein expression was assessed via immunohistochemistry (IHC) on a tissue microarray from 280 colorectal cancer cases. IHC scores were evaluated by digital image analysis and compared with patients' outcomes. In addition, we examined DNA hypermethylation in colorectal cancer cell lines and tissues, which were matched with adjacent normal colon samples.Results: USP10 expression (USP10 loss ) was lost in 18.6% of samples (52/280 cases), which was linked to lymphovascular invasion ( p =0.019) and distant metastases ( p <0.001). Similarly, loss of p14ARF expression (p14ARF loss ) was associated with more advanced tumors. USP10 expression correlated positively with p14ARF expression ( r =0.617, p <0.001). USP10 loss , p14ARF loss , and loss of both USP10 and p14ARF (USP10 loss /p14ARF loss ) were significantly associated with shorter disease-free survival and overall survival in comparison to USP10 intact , p14ARF intact , and USP10 intact /p14ARF intact , respectively. Multivariate analysis revealed that USP10 loss (Hazard ratio=2.07, p =0.046) and USP10 loss /p14ARF loss (Hazard ratio=1.41, p =0.010) are independent prognostic factors for disease-free survival in colorectal cancer patients. Furthermore, aberrant hypermethylation of the USP10 promoter region was found in colorectal cancer cell lines and tissues.Conclusions: The present results suggest that USP10 loss is a potential prognostic marker for colorectal cancer.