This multicenter study explored the survival benefits of upfront primary tumor resection (PTR) followed by first-line cetuximab plus chemotherapy in real-world patients with wild-type metastatic colorectal cancer (mCRC). Treatment options for mCRC include chemotherapy, targeted therapy, immunotherapy, and surgery. The efficacy of upfront PTR in managing mCRC remains unclear. In this retrospective study, we evaluated the outcomes of upfront PTR in 582 patients with synchronous wild-type mCRC who received cetuximab plus chemotherapy as first-line treatment between November 2016 and August 2020. Of these patients, 364 (62.5%) underwent upfront PTR (PTR group) and 218 (37.5%) did not (non-PTR group). Relevant data were collected from 14 medical institutions in Taiwan. No significant differences were discovered between the PTR and non-PTR groups in median overall survival (37.9 vs. 31.7 months; = 0.079) or progression-free survival (13.70 vs. 13.29 months; = 0.62). Compared with patients who did not undergo metastasectomy, those who underwent this surgery exhibited significantly longer median overall survival (29.2 vs. 54.18 months; < 0.001) and progression-free survival (12.8 vs. 15.60 months; = 0.013). Our findings suggest that upfront PTR may not improve oncological outcomes in patients with synchronous wild-type mCRC. Cetuximab-based targeted therapy plus chemotherapy appears to be suitable as first-line treatment for these patients. This study indicates that upfront PTR should be considered only for patients exhibiting symptoms such as tumor bleeding, perforation, or obstruction.