Background: Recently, early tumor shrinkage (ETS) was reported to predict outcome in metastatic colorectal cancer treated with cetuximab (cet). This study was to evaluate the impact of ETS on long-term outcome in patients (pts) with wild-type-KRAS unresectable CLLM receiving cet plus chemotherapy (CT, FOLFIRI or mFOLFOX6). Methods: 138 pts treated in a randomized controlled trial (70 in armA received CT plus cet and 68 in armB received CT alone) previously reported (Jianmin et al, ESMO 2012, abstract-557, ClinicalTrials.gov, number NCT01564810) were included into this analysis. ETS was defined as a reduction of ≥20% in the sum of the longest diameters of target lesions compared to baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and overall survival (OS). Results: 132 pts were available for evaluation, and ETS occurred more frequently in armA than that in armB (45/68 vs. 26/64, p= .003). Irrespective of treatment arm, pts achieved ETS were associated with longer OS (armA: 38.0 vs. 18.7months, p< .001; armB 30.6 vs.17.7months, p= .003) and PFS (armA: 11.8 vs. 4.8months, p< .001; armB 8.0 vs.4.6months, p= .001) when compared to pts with no-ETS. Among pts with ETS, there were statistic difference between armA and armB in terms of PFS (11.8 vs. 8.0months, p= .041) but not of OS (38.0 vs. 30.6months, p= .30); the converted resection rates for liver metastases were 40.0% (18/45) in armA and 19.2% (5/26) in armB, which were no significantly different (p= .072). For pts without liver surgery, pts observed ETS also gained an increased survival benefit over those no-ETS in armA with regards to OS (p= .01) and PFS (p< .001) though it was not full certified in armB (OS: p= .054; PFS: p= .041). For pts in armA, cet-induced skin toxicity correlated with the occurrence of ETS (p= .048). In addition, cox regression for OS using indicated a hazard ratio of 0.39 (95%CI 0.21–0.72, p = .003). Conclusions: ETS ≥20% at 8 weeks may serve as a predictor of favorable outcome in pts with wild-type-KRAS CLLM receiving cet plus CT.