As a common gastrointestinal tumor, colorectal cancer (CRC) in incidence is second only to gastric cancer and esophageal cancer. Abnormal ubiquitination plays an important role in the initiation and development of CRC, but the ubiquinone of CRC and survival-relevant ubiquitination are poorly understood. Here, we examined the proteome and ubiquintome of six CRC patients and found that ubiquitination of 1394 proteins were up-regulated and 1114 proteins was down-regulated in CRC tissues versus para-cancerous tissues. Through the enrichment analysis, we found that the differentially ubiquitinated proteins were related to metabolism, immune regulation and telomere maintaining. In addition, we found that among all the ubiquitinated proteins, highly ubiquitinated proteins (n > 10) accounted for the total 2%, among which PRKDC, PARP14 and SLC12A2 were the most modified proteins. Meanwhile, compared with low-modified proteins, high-modified proteins were more involved in the biological processes such as G-protein coupling, glycoprotein coupling and antigen presentation. Besides we found five motif sequences that were easily modified by ubiquitin. Furthermore, we revealed that FOCAD was related to overall survival rate of CRC (p = 0.038) and the ubiquitination of FOCAD on 583K and 587K was potentially related the down-regulation of FOCAD in CRC. Moreover, we verified the expression of FOCAD in CRC patients using the public database (n = 100). Finally, we elucidated that FOCAD was possibly involved in RNA localization and translational pathways in CRC. The findings in this study provided functional context of ubiquintome in CRC, revealed abnormal ubiquitination potentially affected patient survival, and offered new opportunities for clinical treatment.