BACKGROUND: Early radiological tumor shrinkage may be associated with better long-term outcome in chemorefractory metastatic colorectal cancer (cmCRC) treated with cetuximab. We aimed at validating this in a large and independent series. PATIENTS AND METHODS: Of the 329 patients, 289 had a measurement both at baseline and week 6. Tumor shrinkage was expressed as a relative decrease compared with baseline and categorized according to a previously reported cut-off value ( approximately 10%) or used as a continuous variable. RESULTS: Median time to progression (TTP) was 6.1 [95% confidence interval (CI) 5.1-7.2] versus 1.5 months (95% CI 1.4-1.7) in patients with [99 patients (34.3%)] or without [190 patients (65.7%)] tumor shrinkage, respectively, at week 6 [hazard ratio (HR) 0.23 (95% CI 0.17-0.32)]. The median overall survival (OS) was 13.7 (CI NA) versus 6.9 months (95% CI 6.1-7.7) [HR 0.21 (95% CI 0.14-0.32)], respectively. In a multivariate model, early tumor decrease outperformed skin toxicity as a predictor of long-term outcome. CONCLUSIONS: Tumor shrinkage at 6 weeks is a strong predictor of TTP and OS in cmCRC patients treated with cetuximab with or without irinotecan. This suggests early tumor shrinkage is the hallmark of efficacy of cetuximab and reliably identifies the subpopulation that is sensitive to the drug. Early tumor shrinkage can be used as a marker of efficacy in clinical practice, as such or in combination.