Background: In the recent years, primary tumor location (PTL) is considered as an important prognostic and predictive factor in first-line treatment of mCRC. Although regorafenib (REG) and trifluridine/tipiracil (TFTD) have been available recently, the prognostic value of PTL in later-line with these agents is not well understood. TFTD improved survival regardless of PTL in the RECOURSE trial, while REG did not show survival benefit in the patients (pts) with rectal cancer in the CORRECT trial. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG and TFTD. The impact of PTL on overall survival (OS) were evaluated using Cox proportional hazards models based on baseline characteristics and propensity score matching. Results: A total of 550 pts (223 pts in the REG group, 327 pts in the TFTD group; 122 pts in the right-sided, 428 pts in the left-sided) were included in this study. Although the right-sided pts was significantly shorter OS compared with the left-sided pts by univariate analysis (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.63-0.99, P = 0.04), multivariate analysis revealed that PTL was not an independent prognostic factor (HR 0.88, 95% CI 0.69-1.1, P = 0.26). The similar results were obtained in each treatment group. In subgroup analysis according to PTL, OS were comparable between REG and TFTD groups regardless of PTL (HR 0.93, 95% CI 0.62-1.39 in the right-sided; HR 1.08, 95% CI 0.83-1.39 in the left-sided [excluding rectum]; and HR 1.01, 95% CI 0.62-1.62 in the rectal cancer pts). These results were similar in sensitivity analysis using propensity score-matching. Conclusions: In the present study, PTL is not a prognostic factor in patient with mCRC treated with either REG or TFTD as later-line. No difference in OS was observed between REG and TFTD groups irrespective of PTL.