Purpose <p>Regorafenib improves the survival of patients with metastatic colorectal cancer (mCRC). However, proteinuria frequently occurs in regorafenib treatment, and development of severe hypertension, which is closely related to proteinuria, is associated with better treatment outcomes. We previously reported that patients with baseline proteinuria exhibit regorafenib-induced problematic symptoms. In this study, we aimed to assess the effect of baseline proteinuria on the treatment efficacy of regorafenib for mCRC.</p> Methods <p>Patients with mCRC receiving regorafenib (<i>n</i> = 100) were categorized into control (without baseline proteinuria) and pre-existing proteinuria (baseline grades 1–2) groups and retrospectively evaluated. The primary endpoint was the progression-free survival (PFS).</p> Results <p>Patients in the pre-existing proteinuria group exhibited significantly worse PFS than those in the control group (median with 95% confidence interval [CI] = 51 (46–56) and 56 (49–81) days, respectively; <i>P</i> = 0.04). Overall survival and disease control rate were lower in the pre-existing proteinuria group than in the control group although the difference was not statistically significant (<i>P</i> = 0.11 and 0.10, respectively). Similar results were obtained in the propensity score–matched population. Multivariate Cox hazard regression analyses revealed that baseline pre-existing proteinuria was associated with poor PFS (adjusted hazard ratio = 1.67; 95% CI = 1.03–2.72; <i>P</i> = 0.04). Additionally, ratio of drug suspension duration during all treatment cycles was higher in patients with pre-existing proteinuria than those without symptoms.</p> Conclusion <p>Our results suggest that patients with baseline proteinuria experience poor PFS following regorafenib treatment for mCRC, although we should consider the clinical significance of the difference.</p>