Background: Adjuvant chemotherapy in stage II colorectal cancer (CRC) is generally not recommended. Patients (pts) with T4 tumors, performations, < than 12 lymph nodes assessed, or positive vessel / lymphatic invasion may receive adjuvant chemotherapy. Following these guidelines 15-20% of the true high-risk pts remain undetected, undertreated and will suffer from progression of disease. We previously reported on the validation of a prognostic 32-gene signature (Predictor-C) in a cohort of 164 pts with CRC of stage II and III (J Clin Oncol 28:15s, 2010 (suppl; abstr 3612). Methods: For this study 292 pts with stage II disease underwent curative resection (R0) between 1990-2000 in medical centers of Denmark, Finland, Germany, Austria, Netherlands and Canada. From all pts frozen CRC tissue, clinical data and a follow-up data of five years were available. Gene expression data were obtained using U133 Plus 2.0 arrays from Affymetrix. Results: In this cohort 49/292 pts suffered from a progression of disease, while 243/292 pts had no progression. Applying Predictor-C to this set of 292 UICC stage II pts we observed the following performance chararacteristics: sensitivity of 0.55 (95% CI: 0.402-0.693), specificity of 0.76 (95% CI: 0.706-0.816), positive predictive value (PPV) of 0.32 (95% CI: 0.224 -0.432), negative predictive value (NPV) of 0.89 (95% CI: 0.844-0.932). The point estimate for progression-free survival at 5 years after surgery for pts classified as low-risk is 0.91 (95% CI: 0.772-0.962), and for pts classified as high-risk this estimate is 0.73 (95% CI: 0.630-0.825). The hazard ratio is 3.289 (95% CI: 1.839-5.881), log-rank test and Wilcoxon test of survival times result in p-values < 0.001. The baseline characteristics of these 292 pts were representative for the whole population of CRC patients diagnosed with UICC stage II, in almost all aspects. Conclusions: Predictor-C was successfully evaluated in an independent set of 292 pts with CRC of UICC stage II. Our genomic risk classifier improves the management of pts with stage II after surgery. Low-risk pts identified by Predictor-C may not need adjuvant chemotherapy while high-risk pts may benefit from additional chemotherapy.