Updated project metadata. Relapse and metastatic progression is a frequent event in colorectal cancer patients detected at early stages. The risk of recurrence requires the development of new biomarkers to correctly predict biological behavior of early stage II and stage III patients and their response to adjuvant chemotherapy. Here, we combined the proteomic quantification of secreted proteins involved in metastasis with a transcriptional analysis to develop a risk score algorithm based on the expression of six genes (SEC6). The SEC6 signature was predictive of survival and recurrence for stage II and III patients in four different datasets including a total of 1534 patients and was also associated with deficient mismatch repair, CpG-island methylator positive status and BRAF mutation. SEC6 was also predictive of beneficial or detrimental effects from 5-Fluorouracil-containing regimes and the improved response to more aggressive chemotherapies based on FOLFOX and FOLFIRI. In summary, the SEC6 risk-score algorithm may constitute a new tool for decision-making in colorectal cancer management.