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The aim of the present study was to determine the prognostic significance of a novel marker, the red cell distribution width to lymphocyte percentage (RDW-to-LYM%) ratio, in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). The clinical and follow-up data of 625 patients with UTUC receiving RNU were retrospectively analyzed. The optimal cut-off value of the pre-treatment RDW-to-LYM% ratio was determined as 0.80 using receiver operating characteristic (ROC) analysis according to cancer-specific death. The associations between low (≤0.80) and high (>0.8) RDW-to-LYM% ratio and other clinicopathological parameters were evaluated using the χ 2 test and logistic regression analysis. The impact of the RDW-to-LYM% ratio on overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates was assessed using the Kaplan-Meier method and Cox regression analysis. A high RDW-to-LYM% ratio (>0.80) was significantly associated with impaired kidney function, previous/concurrent bladder cancer, tumors involving both the pelvis and ureter, advanced pathological T stage, lymph node involvement and lymphovascular invasion (LVI). Kaplan-Meier analysis revealed that a high RDW-to-LYM% ratio was associated with poorer OS, CSS and PFS than a low RDW-to-LYM% ratio (all P<0.001). The multiple logistic regression analysis revealed that high RDW-to-LYM% ratio was associated with non-organ-confined (NOC) disease [odd ratio (OR), 2.107; 95% confidence interval (CI), 1.446-3.069; P<0.001] and positive LVI (OR, 1.978; 95% CI, 1.338-2.916; P<0.001). Furthermore, the multivariate analysis showed that the RDW-to-LYM% ratio was an independent factor for predicting OS [hazard ratio (HR), 2.046; P<0.001], CSS (HR, 2.041; P<0.001) and PFS (HR, 1.502; P=0.009). In conclusion, the pre-treatment RDW-to-LYM% ratio was found to be a significant predictor of both NOC and the presence of LVI in patients with UTUC. Moreover, an elevated pre-treatment RDW-to-LYM% ratio was identified as an independent factor for unfavorable survival outcomes in patients with UTUC undergoing RNU., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Hsieh et al.)