Background: Financial toxicity (FT) is a patient-reported outcome measure (PROM), defined as the detrimental effect of financial burden caused by a cancer diagnosis on a patient’s well-being. Although FT is common among cancer patients, little is known about FT following radical cystectomy for bladder cancer in countries with universal health coverage. We aimed to assess de novo FT and its impact on health-related quality of life (HRQOL) in a large prospective cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: 1606 consecutive patients who underwent RC at a large tertiary care center were included. PROMs were prospectively assessed preoperatively, postoperatively at 3mo, then annually until a maximum follow-up of 120mo, applying the validated EORTC QLQ-C30 questionnaire, and the bladder cancer-specific QLQ-BLM30 and FACT-BL-questionnaires. FT was assessed by the “financial toxicity subscale” (FTS) of the EORTC QLQ-C30. Based on previous reports, meaningful FT was defined as FTS ≥ 17. Multivariable regression analysis was used to identify predictors for the development of de novo FT. Separate modeling of longitudinal HRQOL was performed for patients with de novo FT (FT-cohort) and without FT (no-FT-cohort). Results: 93 Patients reporting FT prior RC were excluded from further analysis. 37.6% of the included patients reported de novo FT within 12 months after RC with a mean FTS-score of 55.2 (SD 26.3). Baseline clinicopathological characteristics did not differ between the FT-cohort and the no-FT-cohort (p-range .072-.370). Multivariable logistic regression analysis revealed male gender (OR 3.448, 95%CI 1.10-11.49, p=.045), urban neighborhood (OR 1.532, 95%CI 1.01-2.53, p=.049), a positive smoking history (OR 2.491, 95%CI 1.18-5.26, p=.017) and ileal conduit urinary diversion (OR 2.179, 95%CI 1.03-4.61, p=.042), to independently predict de novo FT following RC. Longitudinal analysis of HRQOL revealed no significant difference in baseline general HRQOL assessed by the global health status domain (GHS) between both cohorts (p=.934). Postoperatively, patients with de novo FT reported significantly worse general HRQOL compared to patients without FT (p= .001). In the longer term, the FT-cohort reported significantly worse GHS scorer up to 84mo after RC. Conclusions: The current study provides prospective data from a unique contemporary patient cohort, which reveals independent predictors for de novo FT following RC. Furthermore, it displays the natural course of general HRQOL for patients who develop de novo FT.