Background: In primary analysis from the TRUSTY study, trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) failed to show non-inferiority to irinotecan and fluoropyrimidine plus BEV in overall survival (OS) as second-line treatment in patients (pts) with metastatic colorectal cancer (mCRC) (median OS, 14.8 vs. 18.1 months: HR, 1.38: 95% CI; 0.99-1.93: p = 0.59 for non-inferiority; Kuboki Y, et al. ASCO 2021). Here we report a post hoc efficacy analysis by baseline tumor burden. Methods: Pts with histologically confirmed mCRC who failed first-line chemotherapy with fluoropyrimidine and oxaliplatin plus either BEV or an anti-EGFR antibody were eligible. Pts were randomized to receive either FTD/TPI plus BEV (FTD/TPI plus BEV group, FTD/TPI 35 mg/m² twice daily on days 1–5 and 8–12 every 28-day cycle, and BEV 5 mg/kg on days 1 and 15) or either FOLFIRI or S-1 and irinotecan combined with BEV (control group). Efficacy measured by OS, progression-free survival (PFS), and disease control rate (DCR) were compared between pts grouped by baseline sum of diameter of target lesions (STL). Survival curves were drawn by direct survival estimation adjusted for stratification factors. Results: In the ITT population (N = 396), 60 mm was selected as the optimal cutoff for STL because it produced the most significant difference in OS; 151 pts had high tumor burden with STL ≥ 60 mm (FTD/TPI plus BEV, n = 76: control, n = 75), 216 had low tumor burden with STL < 60 mm (n = 107, n = 109), and 29 were excluded due to no measurable lesions. Baseline characteristics in pts with both high and low tumor burden were balanced between treatment groups. In pts with STL ≥ 60 mm, FTD/TPI plus BEV was less effective than the control: adjusted median OS was 10.9 versus 16.2 months (HR: 2.32; 95% CI: 1.42-3.79), median PFS was 3.5 versus 6.1 months (HR: 2.32; 95% CI: 1.52-3.53): and DCR was 53.9% versus 72.0% (p = 0.03). In pts with STL < 60 mm, FTD/TPI plus BEV was comparably effective to the control: median OS was 21.4 versus 20.7 months (HR: 0.92; 95% CI: 0.55-1.55), median PFS was 5.6 versus 6.0 months (HR: 1.23; 95% CI: 0.87-1.72), and DCR was 66.4% versus 71.6% (p = 0.46). Conclusions: FTD/TPI + BEV might be a second-line treatment option for mCRC pts with low tumor burden (STL < 60 mm). Clinical trial information: jRCTs031180122.