Uncertainty exists regarding Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab or bevacizumab. We conducted a prospective cohort study comparing PROs and HRQoL from both therapies. This study included 44 patients treated for the first time with one of the strategies, whose PROs scoring for internationally validated questionnaires were compared at three sequential timepoints: baseline, 6-week, and 12-week assessments.