Background: TAS-102 is one of the standard treatments for refractory metastatic colorectal cancer (mCRC). Add-on bevacizumab to TAS-102 has been proved to improve progression-free survival (PFS) and overall survival (OS). However, the two strategies of combination with anti-EGFR or anti-VEGF in RAS/RAF wild-type mCRC patients have not been compared. Methods: We retrospectively collected mCRC patients who received TAS-102 treatment from December 2018 to March 2023 at National Taiwan University Hospital. The key inclusion criteria included RAS/RAF wild-type, first-line treatment with anti-EGFR therapy, and TAS-102 in combination with anti-EGFR re-challenge, or with anti-VEGF therapy. Concurrent use of other chemotherapies was allowed. The patients with combination duration less than 4 weeks were excluded. Results: A total of 30 patients were enrolled. There were 20 patients who received TAS-102 plus anti-EGFR re-challenge, and 10 were treated with TAS-102 plus anti-VEGF. The median treatment line of TAS-102 combined with targeted therapies was 5 (Range 3-11). There was no significant difference in baseline characteristics between the two groups (Table). For TAS-102 plus anti-EGFR vs VEGF, the ORR was 30.0% vs 0%, and the DCR was 70.0% vs 30.0%, respectively. The median PFS was 4.0 vs 2.3 (p=0.389) months, respectively. The median OS was 12.67 vs 9.93 (p=0.722) months, respectively. Conclusions: TAS-102 plus anti-EGFR re-challenge showed a higher ORR than TAS-102 plus anti-VEGF. The PFS and OS were comparable in both arm and numerically longer in the TAS-102 plus anti-EGFR re-challenge group.