Abstract: Objective To compare the efficacy and prognosis of oxaliplatin-based regimens and FOLFIRI regimen as the first-line chemotherapy for stage Ⅳ colorectal cancer patients with different K-ras statuses. Methods We collected clinical data of 118 stage Ⅳ colorectal cancer patients treated with oxaliplatin-based regimens or FOLFIRI regimen as the first-line chemotherapy from Jan. 2010 to Jan. 2012. The cumulative survival rate, objective response rate(ORR), disease control rate(DCR), progression free survival(PFS) and overall survival(OS) of the cases were calculated. Chi-square test was used to compare the differences of clinical factors, ORR and DCR between different groups. Kaplan-Meier method was used to compare the differences of PFS and OS. Results Oxaliplatin-based regimens chemotherapy prolonged PFS and OS of the K-ras mutant patients compared with FOLFIRI regimen chemotherapy (P=0.048; P=0.037). ORR and DCR of the K-ras mutant patients treated with oxaliplatin-based regimens chemotherapy were not significantly different from those with FOLFIRI regimen chemotherapy (P=0.961; P=0.931). ORR, DCR, PFS and OS of the K-ras wide type patients treated with oxaliplatin-based regimens chemotherapy were not significantly different from those with FOLFIRI regimen chemotherapy (P=0.900; P=0.802; P=0.738; P=0.904). Conclusion Oxaliplatin-based regimens as the first-line chemotherapy is more beneficial than FOLFIRI regimen as the first-line chemotherapy for K-ras mutant stage Ⅳ colorectal cancer patients; however, the efficacy and prognosis of K-ras wild type stage Ⅳ colorectal cancer patients were not significantly different between oxaliplatin-based regimens and FOLFIRI regimen chemotherapy.