Simple SummarySynchronously metastasized colorectal cancer (mCRC) is a disease with high morbidity and mortality; therefore, urgent therapeutic decisions are necessary. In recent years, the therapeutic strategies and outcomes have improved due to systemic and local therapies. The primary aim of this retrospective study was to assess the pathological response of the primary tumor, comparing different antibody combinations with chemotherapy in potentially resectable patients. The long-term effect of initial and postoperative therapies was analyzed with recurrence-free survival (RFS) and overall survival (OS) as the endpoints. In this study, we were able to demonstrate a statistically significant better pathological response of the primary tumor and a significantly longer RFS for patients who received vascular endothelial growth factor (VEGF) antibody-based induction chemotherapy compared to patients who received epidermal growth factor receptor (EGFR) antibody-based therapy. These findings are clinically relevant for a prospective evaluation.Abstract(1) Background: The pathological tumor response of the primary tumor to induction chemotherapy in synchronously metastasized colorectal cancer (mCRC) patients has not been investigated. The aim of this study was to compare patients treated with induction chemotherapy combined with vascular endothelial growth factor (VEGF) or with epidermal growth factor receptor (EGFR) antibodies. (2) Methods: We present a retrospective analysis, where we included 60 consecutive patients with potentially resectable synchronous mCRC who received induction chemotherapy combined with either VEGF or EGFR antibodies. The primary endpoint of this study was the regression of the primary tumor, which was assessed by the application of the histological regression score according to Rödel. The secondary endpoints were recurrence-free survival (RFS) and overall survival (OS). (3) Results: A significantly better pathological response and a longer RFS for patients treated with the VEGF antibody therapy compared to those treated with the EGFR antibodies was demonstrated (p= 0.005 for the primary tumor and log-rank = 0.047 for RFS). The overall survival did not differ. The trial was registered with clinicaltrial.gov, number NCT05172635. (4) Conclusion: Induction chemotherapy combined with a VEGF antibody revealed a better pathological response of the primary tumor, leading to a better RFS compared to that with EGFR therapy; this has clinical relevance in patients with potentially resectable synchronously mCRC.