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Summary: The tumor, nodes and metastasis (TNM) classification system provides useful but incomplete prognostic information and lacks the assessment of the tumor microenvironment (TME). Collagen, the main component of the TME extracellular matrix, plays a nonnegligible role in tumor invasion and metastasis. In this cohort study, we aimed to develop and validate a TME collagen signature (CSTME) for prognostic prediction of stage II/III colorectal cancer (CRC) and to compare the prognostic values of “TNM stage + CSTME” with that of TNM stage alone. Results indicated that the CSTME was an independent prognostic risk factor for stage II/III CRC (hazard ratio: 2.939, 95% CI: 2.180–3.962, p < 0.0001), and the integration of the TNM stage and CSTME had a better prognostic value than that of the TNM stage alone (AUC(TNM+CSTME) = 0.772, AUC TNM = 0.687, p < 0.0001). This study provided an application of “seed and soil” strategy for prognosis prediction and individualized therapy.