Background <p>Trifluridine/Tipiracil (FTD/TPI) combined with bevacizumab (Bev) is a standard treatment for patients with unresectable metastatic colorectal cancer (mCRC) in later-line therapy. Despite the availability of other drugs like regorafenib and fruquintinib, there is no consensus on the optimal treatment choice or sequence for later-line therapies due to a lack of clearly defined prognostic indicators. This multicenter real-world analysis aimed to identify predictive factors related to the effectiveness of FTD/TPI + Bev.</p> Patients and methods <p>We retrospectively analyzed the medical records from our institution and collaborating centers of 71 mCRC patients given FTD/TPI + Bev as third-line or later treatment. Survival data were calculated using the Kaplan–Meier method, and group comparisons were made using the log-rank test. Multivariate analyses of progression-free survival (PFS) and overall survival (OS) were performed using a Cox proportional-hazards model.</p> Results <p>A performance status (PS) of 0–1, absence of liver metastases, and fewer metastatic sites were significantly associated with improved PFS. For OS, significant differences were observed according to PS, presence of liver metastases, number of metastatic sites, and <i>RAS/BRAF</i> mutational status. Among patients who received anti-VEGF agents in second-line therapy, those with a second-line PFS of more than 9&#xa0;months had significantly better median PFS and OS with FTD/TPI + Bev compared to those with a median PFS of 9&#xa0;months or less. In multivariate analysis, PS and duration of second-line PFS were the only significant predictors of PFS and OS.</p> Conclusion <p>The response to anti-VEGF agents in second-line therapy may predict the efficacy of FTD/TPI + Bev in subsequent treatments.</p>