Background The aim of this study was to perform an accurate exploration on the efficacy of oxaliplatin/5-fluorouracil/capecitabine-cetuximab combination therapy and its effects on K-Ras mutations in advanced colorectal cancer. Material/Methods Among 96 patients who suffered metastatic colorectal cancer without mutated K-Ras , 41 patients who were receiving treatment with oxaliplatin/5-fluorouracil/capecitabine and administered cetuximab as the initial treatment comprised the observation group; the remaining 55 patients receiving cetuximab as an alternative treatment comprised the control group. Results The observation group experienced significantly higher objective response rates (ORRs), and disease control rates (DCRs), than the control group ( P <0.05 for both). The median progression-free survival (PFS) rates of the observation group and the control groups were 11.2 months (95% confidence interval [CI]: 10.1–12.3 months) and 7.4 months (95% CI: 6.6–8.2 months). The median overall survival (OS) rates were 16.8 months (95% CI: 15.2–18.4 months) and 12.4 months (95% CI: 11.6–13.2 months), respectively. The observation group had significantly longer PFS and OS in comparison to the control group ( P <0.05). The patients who underwent cetuximab treatment for ≥10 months had a slightly higher rate of K-Ras mutations than those treated with cetuximab for <10 months (9.1% versus 7.3%). Conclusions Oxaliplatin/5-fluorouracil/capecitabine plus cetuximab exhibited better efficacy as initial treatment than the alternative treatment; it was also highly safe. Unfortunately, some patients might develop K-Ras mutations after long duration of cetuximab treatment, suggesting that K-Ras mutations are correlated with tumor progression and depend on the duration or dose of cetuximab treatment.