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Background Several studies report aberrant expression of sine oculis homeobox (SIX) homolog family members during cancer development and progression. SIX4 participates in organ development, such as myogenesis and neurogenesis. However, the expression and clinical implication of SIX4 in colorectal cancer (CRC) remains unclear. Methods The SIX4 expression levels in colorectal patients were assessed in nine different human cancer arrays and compared using patient survival data. SIX4 expression was silenced in two cell culture lines for invasion and wound healing assessment. Finally, bioinformatics assessments ascertained the pathways impacted by SIX4. Results SIX4 was upregulated in The Cancer Genome Atlas CRC cohort and other gene expression omnibus (GEO) cohorts. In addition, SIX4 expression significantly correlated with lymph node metastasis and advanced Tumor Node Metastasis (TNM) stages. Moreover, SIX4 overexpression was related to unfavorable prognosis in CRC patients. Silencing SIX4 inhibited CRC cell metastasis by surpressing AKT phosphorylation. Discussion SIX4 is upregulated in CRC and can be used as a prognosis biomarker.