Abstract Objective To assess the cost effectiveness of cetuximab in third-line treatment of patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) in routine clinical practice compared with best supportive care (BSC). Methods Patients (n = 287) with KRAS wt mCRC treated with cetuximab or BSC in eight hospitals in the Netherlands between 2009 and 2012 were included in our real-world study. Outcome measures were costs per life-year (LY) and costs per quality-adjusted LY (QALY) gained. A Markov model was developed, and a time horizon of four years was applied. Outcomes were calculated from Kaplan-Meier survival curves from patient-level data and literature. Direct medical costs were estimated in all centers (2013 values), and incremental cost-effectiveness ratios (ICERs) were calculated. Results were discounted, and a probabilistic sensitivity analysis was performed. Results Administration of cetuximab in third-line treatment of mCRC resulted in a gain of 0.29 LYs and 0.25 QALYs compared with BSC. In the four-year study period, average discounted healthcare costs were €36,637 in the cetuximab group vs. €3648 in the BSC group. The discounted ICERs of cetuximab vs. BSC in the real-world setting were €114,907and €133,527 per LY and QALY gained, respectively. Conclusions Results of this cost-effectiveness analysis showed that third-line treatment with cetuximab for patients with KRAS (exon 2) wt mCRC offered clinical benefits at additional cost. The real-world ICERs were in line with those of previously published cetuximab and panitumumab cost-utility models.