BACKGROUND: The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated. OBJECTIVE: To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS: The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006. INTERVENTION: Patients were treated with RNU and lymphadenectomy. MEASUREMENTS: Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified. RESULTS AND LIMITATIONS: In the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001). CONCLUSIONS: The extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.