OBJECTIVES: To evaluate health-related quality of life (HRQOL) six years post-radical cystectomy in patients with muscle-invasive bladder cancer, comparing orthotopic ileal neobladder (ONB) and ileal conduit (IC). Therefore, the study aims to analyze the under-investigated long-term impact of standard bladder cancer treatments on HRQOL and provide insights into the HRQOL differences associated with these two common urinary diversion methods. PATIENTS AND METHODS: This prospective study included 39 patients with urothelial carcinoma treated with ONB or IC at our center between 03/2013 and 01/2023. Patients with variant histology, metastasis, neoadjuvant chemotherapy, or benign indications for cystectomy were excluded. HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire preoperatively, at four and six years postoperatively. Statistical analyses included Chi-square tests, T-tests, and logistic regression models. RESULTS: Of the patients, 64% (25/39) underwent ONB, and 76.9% (30/39) were male, with an average age of 69 years. No significant differences in overall good HRQOL (GHS >
70) were observed between ONB and IC at six years (IC: 60 ± 22
ONB: 69 ± 23, p = 0.2). Patients with IC reported higher insomnia at both follow-ups (4 years: p = 0.01
6 years: p = 0.03). Emotional function remained stable in ONB patients but declined in IC patients from the fourth to sixth years (p = 0.04). CONCLUSION: Long-term HRQOL did not significantly differ between ONB and IC up to six years post-radical cystectomy. Both urinary diversion methods can be offered to patients, with tailored discussions in terms of HRQOL.