Colorectal cancer patients with wild-type KRAS were collected and treated with cetuximab and the efficacy was assessed. Paraffin-embedded tumor specimes and clinicopathological parameters were collected and mutations of BRAF and PIK3CA were checked. The PTEN expression status was detected through immunohistochemistry. The study indicates that the objective response rate of patients with wild-type BRAF and PIK3CA is 62.5% (CR+PR). In contrast, the objective response rate of patients with mutation-type BRAF and PIK3CA are 0% and 28.6%, respectively. Therefore, the fact that BRAF and PIK3CA mutations could affect the effective of cetuximab is deducted. And PTEN expression is mainly located in cell nucleus and PTEN expression is associated with the response to cetuximab significantly. The objective response rate of patients with PTEN expression or null are 42.9% and 36.4% (P<0.05), respectively. In conclusion, BRAF, PIK3CA mutations and PTEN expression null both have been associated with resistance to cetuximab. BRAF, PIK3CA, and PTEN could serve as the predictive bio-markers for the response to cetuximab.