Simple SummaryTargeted therapy targeting the EGFr and vascular endothelial growth factor (VEGF) is often combined with chemotherapy in palliative treatment of metastatic colorectal cancer. The aim of this population-based cohort study was to examine factors influencing treatment decisions for targeted therapy and their effect on overall survival in palliative metastatic colorectal cancer. The medical costs of targeted therapy if introduced early or late in the palliative setting were also assessed. The results showed no effect of high medical costs on overall survival for patients with metastatic colorectal cancer. The medical costs are high and especially so if introduced early in the palliative setting. We suggest that targeted therapy be saved for later lines of therapy in patients with palliative colorectal cancer.Abstract(1) Background: Targeted therapy is used alone or together with chemotherapy in metastatic colorectal cancer. The aim of this study was to assess overall survival and medical costs in a cohort of patients with metastatic colorectal cancer. (2) Methods: Demographic and clinical characteristics of 337 patients and pathological data of colorectal tumors were retrospectively collected in this population-based study. The overall survival and medical costs for patients receiving chemotherapy plus targeted therapy were compared with those for patients receiving chemotherapy only. (3) Results: Patients administered chemotherapy plus targeted therapy were less frail and had more often RAS wild-type tumors but had higher CEA levels than patients receiving chemotherapy only. No prolonged overall survival could be observed in patients receiving palliative targeted therapy. The medical costs for patients undergoing treatment with targeted therapy were significantly higher than for patients treated only with chemotherapy; they were especially higher in the group receiving targeted therapy early than late in the palliative setting. (4) Conclusions: The use of targeted therapy in metastatic colorectal cancer leads to significantly higher medical costs when used early in the palliative setting. No positive effects of the use of targeted therapy could be observed in this study; therefore, we suggest that targeted therapy be used in later lines of palliative therapy in metastatic colorectal cancer.