The combination of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAb) and doublet chemotherapy is the standard first-line treatment for patients with wild-type metastatic colorectal cancer (mCRC). Some patients may require secondary resection after first-line treatment. However, it remains unclear whether targeted therapy should be continued after liver resection. To investigate whether targeted therapy can be spared after secondary resection, we retrospectively analyzed data from the Taiwan National Health Insurance Research Database for patients with wild-type mCRC who received first-line anti-EGFR mAb plus doublet chemotherapy. Between 2013 and 2018, 5694 mCRC patients were screened, with 174 meeting the eligibility criteria and being enrolled in this study. Among them, 153 patients continued anti-EGFR mAb after secondary resection. These patients demonstrated a significant improvement in overall survival (OS) but not in time to treatment failure. Postresection anti-EGFR mAb conferred OS benefits compared to no anti-EGFR mAb (43.17 vs. 31.41 months; = 0.0064). When stratified by assessment period, OS was longer in patients assessed between 2016 and 2018 than in those assessed between 2012 and 2015 (not reached vs. 39.87 months; = 0.1819). However, no significant difference was observed in time to treatment failure when stratified by assessment period or primary tumor location. A multivariate analysis revealed that postresection anti-EGFR mAb was an independent predictor of prolonged OS. In conclusion, for mCRC patients who have undergone secondary resection after first-line anti-EGFR mAb plus doublet chemotherapy, continuing anti-EGFR mAb may significantly extend OS, regardless of the primary tumor location.