OBJECTIVES: To evaluate the efficacy and safety of cetuximab in combination with chemotherapy vs. chemotherapy alone for the first-line treatment of metastatic colorectal cancer (mCRC), in patients with KRAS wild-type tumours. METHODS: Two systematic reviews of literature have been conducted. One focused on the efficacy, identifying health technology agencies reports, meta-analysis, systematic reviews, and randomized controlled trials (RCTs). The safety systematic review included the previous designs plus observational studies. In the latter review, studies in subsequent lines of treatment were considered. Searches were done in MEDLINE, EMBASE, CRD, and the Cochrane Library until the 8th of June. The quality assessment of the studies was done with the SIGN and CASPe tools. Two authors independently selected the studies, assessed the quality, and performed the data extraction, with disagreements resolved by a third reviewer until consensus was obtained. RESULTS: In the efficacy systematic review, three RCTs were included. The chemotherapy in one of these trials was FOLFIRI, in another trial FOLFOX-4, and in the other one was oxaliplatin and fluoropyrimidine chemotherapy. In the safety systematic review, five RCTs (3 studies in first-line, one study in second-line and another with cetuximab in monotherapy in subsequent lines), and an observational study were considered. Cetuximab in combination with FOLFIRI improved overall survival (OS), resection rate, progression free survival (PFS) and overall tumour response rate (RR). Whereas, an increase in terms of OS was not observed with cetuximab in combination with oxaliplatin based regimen, and different results were obtained in PFS. The only benefit observed with the later regimen was in the RR. In terms of safety, cetuximab increased grade 3 or 4 skin toxicity. CONCLUSIONS: The benefit of the addition of cetuximab to standard therapy for previously untreated mCRC, KRAS wild-type patients differs depending on the chemotherapy associated, with an improvement in all the outcomes when FOLFIRI is used.