Background: To investigate the prognostic significance of systemic inflammation score (SIS) in upper tract urothelial carcinoma (UTUC) in patients undergoing radical nephroureterectomy (RNU). Methods: A total of 313 UTUC patients who underwent RNU at West China Hospital from May 2014 to June 2019 were retrospectively analyzed. The predictive value of SIS for relevant endpoints, including overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS), was assessed by Kaplan-Meier curves and the Cox proportional hazards model. Results: According to inclusion and exclusion criteria, 218 UTUC patients were ultimately included in this cohort study. Statistical analysis shows that increased SIS was significantly associated with higher TNM stage (p = 0.017), lower BMI (p = 0.037), absence of hemoglobin (p < 0.001), and pathologic necrosis (p = 0.007). Kaplan-Meier survival curves clearly visually stratified survival for the three outcomes. After adjusting for tumor grade, the multivariate Cox proportional hazards model results showed that SIS was an independent risk factor for poor OS and CSS (HR = 1.89, 95% CI: 1.11-3.21, p = 0.0183, HR = 1.89, 95% CI: 1.07-3.33, p = 0.0285) in the advanced group. Conclusions: SIS was an independent risk factor for OS and CSS after RNU in patients with high-grade UTUC. It may be a novel and conducive tool for preoperative risk stratification and guiding individualized therapy for high-risk UTUC patients.