Colorectal cancer (CRC) patients frequently experience disease recurrence and distant metastasis. This study aimed to identify prognostic indicators, including individual responses to chemotherapy, in CRC patients. RNA-seq data was generated using 54 samples (normal colon, primary CRC, and liver metastases) from 18 CRC patients and genes associated with CRC aggressiveness were identified. A risk score based on these genes was developed and validated in four independent CRC patient cohorts (n = 1063). Diverse statistical methods were applied to validate the risk scoring system, including a generalized linear model likelihood ratio test, Kaplan–Meier curves, a log-rank test, and the Cox model. TREM1 and CTGF were identified as two activated regulators associated with CRC aggressiveness. A risk score based on 19 genes regulated by TREM1 or CTGF activation (TCA19) was a significant prognostic indicator. In multivariate and subset analyses based on pathological staging, TCA19 was an independent risk factor (HR = 1.894, 95% CI = 1.227–2.809, P = 0.002). Subset stratification in stage III patients revealed that TCA19 had prognostic potential and identified patients who would benefit from adjuvant chemotherapy, regardless of age. The TCA19 predictor represents a novel diagnostic tool for identifying high-risk CRC patients and possibly predicting the response to adjuvant chemotherapy.