IntroductionUpper tract urothelial carcinoma (UTUC) is a rare malignancy with poor prognosis. Radical nephroureterectomy (RNU) remains the standard treatment for high-risk UTUC. Considering the decline in renal function with RNU and results from prospective trials, NAC has emerged as a favored perioperative treatment for chemo-eligible patients with UTUC. However, strong evidence of the efficacy of NAC and predictors for its use are scarce. We aimed to assess trends in NAC utilization and pathologic outcomes and survival with NAC use. MethodsThe National Cancer Database was queried for patients with high-grade cTanyNanyM0 UTUC treated with RNU from 2004-2019. Outcomes included overall survival (OS), pathologic response (pR) and pathologic complete response (pCR), defined as ≤pT1pN0/X and pT0pN0/X, respectively. ResultsOf 6,645 patients treated with RNU, 209 received RNU NAC. Greater distance from treatment facility decreased the likelihood of receiving NAC. Higher cT stages (OR 1.72, p=0.028), cN+ status (OR 7.40, p<0.001) and treatment at an academic facility (OR 2.02, p<0.001) predicted NAC treatment. NAC was associated with 34.0% pR and 5.3% pCR. In multivariable analysis, patients with pR and pCR had improved OS (HR=0.176, p<0.014). ConclusionWe report significant response rates with NAC and improved OS in patients who experienced pR or pCR. Over a 15-year study period, NAC was underutilized, especially in non-academic settings and among patients living farther from care facilities, underscoring the need for improved regionalization and multi-disciplinary approaches in UTUC management. Micro abstractThis study evaluated neoadjuvant chemotherapy (NAC) utilization and outcomes for patients with upper tract urothelial carcinoma (UTUC) in the National Cancer Database. NAC was underutilized, especially for patients at farther, non-academic centers. NAC use was associated with 5.3% pathologic complete response and improved overall survival in responders. Our findings support NAC benefits and reveal disparities in its use for UTUC.