Background: Prognosis for high grade, non-metastatic upper tract urothelial carcinoma (UTUC) (renal pelvis or ureter) has not improved in past two decades. Given improvements in disease-free survival in phase III POUT study, adjuvant chemotherapy (AC) has been the preferred approach. Neoadjuvant chemotherapy (NAC) is favored based on median survival (OS) benefit seen in urothelial bladder cancer. We studied National Cancer Database (NCDB) to answer this question. Methods: We identified adults > 18 years with non-metastatic, high grade, UTUC. All patients received surgery of the primary site and chemotherapy in the neoadjuvant or adjuvant setting. Patient’s receiving radiation therapy or who died within 90 days of surgery were not included. Descriptive statistics, log-rank tests and cox-regression tests were performed. Patients achieving complete pathological response (pCR) defined as (pTis, pT0, pTa and N0) were assessed for OS. Results: 1191 patients with complete data were identified; 225 (19%) received NAC and 966 (81%) received AC. 60% were males, median age was 68 and 73% had Charlson score (CS) of ‘0’. Median follow-up time for alive patients was 30.4 and 36.7 months in the NAC and AC groups respectively. Renal pelvis was the primary in 760 cases (63%) and ureter in 441 (37%). On univariate analysis receiving NAC, age < 75 years and CS score ‘0’ was associated with significant survival benefit (p < 0.05). Similarly on multivariate analysis receiving NAC and having CS of ‘0’ had significantly better survival with HR 0.75 (CI 0.58-0.96) and 0.8 (CI 0.65-0.96) respectively. Age > 75 years had worse survival HR 1.34 (CI 1.08-1.66). Thirty-seven patients (17%) in the NAC group achieved pCR with OS > 71.6 months which was significantly better than AC group and non-responders in the NAC group (p < 0.05). There was a trend towards more benefit with NAC compared to AC in Stage 1 and 2 UTUC than in Stage 3 and 4. Conclusions: Our study indicates that subset of early stage UTUC benefit more from NAC comparing to AC. However, randomized prospective study is warranted to further explore the role of NAC in UTUC.