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Introduction The natural progression of colorectal cancer differs greatly between patients and metastatic progression is a complex and largely unknown process. After a diagnosis of colorectal cancer (CRC), approximately 50% of patients will present distant metastasis. Although significant progress has been made in treatments, most of them will die from the disease. We investigated the predictive and prognostic potential of APC11, the RING-H2 catalytic subunit of APC/C, which has never been examined in the context of CRC. Material and methods The expression of APC11 was assessed in CRC cell lines, by RT-qPCR and western blot, in tissue microarrays (TMAs) by immunohistochemistry in a chronological series of 82 patients with CRC, and the public CCLE and TCGA datasets. In public datasets, the expression levels of the two other APC/C catalytic subunits, namely APC2 and APC10 were also analysed. To investigate the clinical significance of APC11, multifactorial analyses and multivariable logistic and Cox regression models were performed, accounting for the effects of well-known protein markers involved in the colorectal tumorigenesis, namely Ki67, p53, E-cadherin, Bcl2, MLH1, MSH2, and DCC Results and discussions Overexpression of APC11 mRNA was associated with chromosomal instability (CIN), lymphovascular invasion and residual tumour. No correlation was identified with CIN or residual tumour for APC2 and APC10. Multivariable regression models highlighted association of AP11 protein expression with residual tumour (odds ratio: OR=6.51; 95% confidence intervals: CI=1.54–27.59; p=0.012) and metastasis at diagnosis (OR=3.87; 95% CI=1.20–12.45; p=0.024). Overexpression of APC11 protein was also associated with worse distant relapse-free survival (hazard ratio: HR=2.60; 95% CI=1.26–5.37; p=0.01) and worse overall survival (HR=2.69; 95% CI=1.31–5.51; p=0.007). Conclusion APC11 overexpression in primary CRC is associated with CIN, metastasis at diagnosis, and poor clinical outcomes. Thus, it might represent a novel theranostic marker of metastatic CRC. Clinical management of CRC is still based on TNM classification for therapeutic decisions, and APC11 protein expression may provide a novel, cost-effective, immunohistochemistry-based means of improving personalised therapeutic strategies.