The addition of cetuximab to FOLFIRI or FOLFOX as the first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated systematic meta-analysis was undertaken to determine the efficacy of cetuximab plus FOLFIRI or FOLFOX. Major databases were searched to identify RCTs investigating wild-type KRAS mCRC after the first-line treatment, and treatment with FOLFOX/FORFIRI +/- cetuximab was compared. Data on clinical efficacy and safety were pooled and compared by ORs, HRs, and 95% CIs. Five eligible trials with 1464 patients were included in the meta-analysis. Compared to FOLFOX/FORFIRI +/- cetuximabas the first-line therapy has improved overall survival (OS) (hazard ratio [HR]= 0.82, 95% confidence interval [CI]: 0.72-0.93, P= 0.003), progressionfree survival (PFS) (HR= 0.66, 95% CI: 0.56 -0.77, P< 0.00001), and overall response rate (ORR) ( odds ratio [OR]= 2.12, 95% CI: 1.70- 2.65, P< 0.00001). However, Grade 3/4 AE was increased with the OR of 2.76 ( 95% CI: 2.01-3.78, P< 0.00001). The most common grade 3/4 toxicity in the wild-type KRAS population was neutropenia and diarrhea. For cetuximab plus FOLFIRI, there was a higher incidence of grade 3 or 4 diarrhea (OR=1.76, 95% CI: 1.15-2.70, P= 0.01), but there was no significant difference for neutropenia (OR= 1.35, 95% CI: 1.00-1.83, P= 0.05). The addition of cetuximab in mCRC as the first-line treatment is a potential effective approach in the improved outcomes but associated with increased toxicity.