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OBJECTIVE The aim of this study was to clarify the role of TCF19 in influencing the malignant progression of colorectal cancer (CRC) by negatively regulating WWC1. PATIENTS AND METHODS Relative expression levels of TCF19 and WWC1 in CRC tissues and cells were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The prognosis of CRC patients was assessed by the Kaplan-Meier method. Meanwhile, the correlation between TCF19 and pathological indexes of CRC patients was evaluated. Regulatory effects of TCF19/WWC1 on viability, colony formation ability, and migration in HT29 and HCT-8 cells were evaluated. Finally, rescue experiments were conducted to elucidate a negative feedback loop of TCF19/WWC1 in influencing the progression of CRC. RESULTS TCF19 was significantly up-regulated in CRC, while WWC1 was down-regulated. High-level TCF19 or low-level WWC1 indicated worse survival of CRC patients. Besides, TCF19 expression level was positively correlated with the occurrence of distant metastasis in CRC. Silence of TCF19 significantly attenuated proliferative and migratory capacities of HT29 cells. However, overexpression of TCF19 yielded the opposite trends in HCT-8 cells. WWC1 expression was negatively regulated by TCF19 in CRC tissues. In addition, knockdown of WWC1 abolished the regulatory effect of TCF19 on CRC cells. CONCLUSIONS TCF19 is closely correlated with the occurrence of distant metastasis and poor prognosis of CRC. Furthermore, it aggravates the malignant progression of CRC via negatively regulating WWC1.