Background: Previous studies have shown pronounced gender specific differences regarding diagnosis and oncological outcome for patients with bladder cancer (BC). Current literature lacks evidence on gender specific differences in health-related quality of life (HRQOL) outcomes for patients with BC following radical cystectomy (RC). We aimed to assess those gender specific differences by providing HRQOL data from a large prospective propensity score-matched cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: 1498 consecutive patients [n=421 women, n=1077 men] who underwent RC at a large tertiary care center were included. A propensity-score matched analysis of 794 patients [n=397 women, n=397 men] was conducted applying the matching- variables “patient age”, “BMI”, “pT-stage” and “type of urinary diversion”. Exclusion criteria encompassed age <30 yr and RC due to benign diseases. HRQOL was assessed preoperatively, at 3 mo, then annually until a maximum follow-up of 120 months applying the validated EORTC QLQ-C30- as well as the bladder cancer-specific QLQ-BLM30- and FACT-BL-questionnaires. Separate modeling of longitudinal HRQOL for women and men was performed. Spearman’s rank correlation was applied to identify gender specific factors influencing HRQOL. Results: At baseline women and men showed no significant difference in general HRQOL assessed by the global health status domain (GHS) (p=.162). Women presented with worse mean emotional (p=.001) and cognitive (p=.007) functioning subscale. In the longitudinal analysis, a similar natural course of the GHS for women and men could be observed up to 36mo after RC (p-range: .107 - .856). Between 48mo and 96mo after RC, general HRQOL was significantly higher for men compared to women (p-range: .002-.045). At 12month a significant correlation between physical functioning or urinary continence and increased general HRQOL could equally be observed for men and women (each p< .05). No significant correlation was found between sexual functioning and increased general HRQOL. While a strong correlation between Social/Family wellbeing and increased general HRQOL was found for women (p=.001), no correlation was found for men (p=.103). Conclusions: The current study provides prospective data from a unique propensity score-matched contemporary patient cohort, which displays gender specific differences in the natural course of general HRQOL and its subdomains. Those data are important to guide gender specific treatment decision-making for patients with BC.