TRAF-interacting protein (TRAIP) is a RING-type E3 ubiquitin ligase which has been implicated in various cellular processes, including NF-κB activation, DNA damage response, mitosis, and tumorigenesis. It is considered as a tumor suppressor in basal cell carcinomas and breast cancer in previous studies. However, in our current study, we found that TRAIP exhibited oncogenic properties in liver cancer. In order to determine its effect on tumor biology and the potential mechanism, a variety of advanced experimental technology was used, such as bioinformatic analysis, isobaric tags for relative and absolute quantification (iTRAQ) analysis, tissue microarray detection, and other in vitro cell biology experiments. The results showed that TRAIP was up-regulated in liver cancer and negatively correlated with prognosis. When TRAIP was knocked-down with lentivirus containing specific targeting short hairpin RNAs, the malignant behaviors of Bel7404 cells were significantly inhibited. Meanwhile, overexpression of TRAIP exerted oncogenic effects in SNU449 cells. More importantly, the iTRAQ analysis indicated that TRAIP was significantly related to centriole, centromere, and histone deacetylation, which are critical for mitosis. These findings are in line with previous reports that TRAIP contributes to proper mitosis. Additionally, the iTRAQ analysis also supported that TRAIP may affect G1/S transition by regulating the expression of certain cell cycle related proteins. In summary, our study firstly revealed that TRAIP was up-regulated and negatively correlated with prognosis in liver cancer patients and exhibited oncogenic properties in liver cancer cells, making it a potential target for treatment of liver cancer.