Abstract: Objective To explore the efficacy of first-line chemotherapy and targeted therapy in advanced colorectal cancer patients with K-ras gene mutations. Methods Clinical data about 55 advanced colorectal cancer patients with K-ras gene mutations who received therapy in our hospital from January 2008 to December 2013 were retrospectively analyzed. Results Follow-up was done till December 31, 2013, of the 55 patients, 45 patients (81.8%) died, the median overall survival (mOS) was 14.4 months, the median progression free survival (mPFS) was 5.7 months, and the 1-year survival rate was 66%. In terms of objective response rate, the firstline chemotherapy Oxaliplatin group had a better ORR compared with Irinotecan group (32% vs.23.1%), while the Irinotecan + BEV group had a better ORR compared with Irinotecan group (37.5% vs.23.1%), but the difference was not statistically significant. In terms of disease control rate, the Irinotecan + BEV group had a better DCR compared with Irinotecan group (100% vs.84.6%) with no statistically significant difference. Conclusion Oxaliplatin-based chemotherapy is more conductive to improve objective response rate for K-ras gene mutations patients, chemotherapy combined with bevacizumab shows some effect on prolonging survival time of K-ras gene mutations patients.