INTRODUCTION: It is unknown whether sex-related differences in response to neoadjuvant (NAC) or adjuvant chemotherapy (ADJ) exist in urothelial carcinoma patients treated with radical cystectomy (RC). We addressed these knowledge gaps. MATERIAL AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2007-2020), we identified NAC candidates (T2-T4N0M0) and ADJ candidates (T3-T4 and/or N1-3). We divided patients according to sex (male versus female). Subsequently, within NAC-candidate patients, survival analyses consisted of Kaplan-Meier plots and multivariable Cox regression models (MCR) addressing cancer-specific mortality (CSM) according to NAC-exposed versus RC alone. We repeated the same methodology in ADJ-candidate patients. RESULTS: We identified 5,745 NAC candidates, of whom 1,278 were female (22%) and 4,467 were male (78%). Among these, NAC was administered in 247 (19%) females and 986 (22%) males. In females, NAC exposure independently predicted lower CSM rates relative to RC alone (HR: HR:0.73, P = 0.03). In males, NAC exposure also independently predicted lower CSM rates, but to greater extent (HR:0.65, P <
0.001). Similarly, we identified 7,283 ADJ candidates, of whom 1,659 (23%) were females versus 5,624 (77%) males. Among these, ADJ was administered in 365 females (22%) and 1,326 (24%) males. In females, ADJ exposure independently predicted lower CSM rates relative to RC alone (HR:0.81, P = 0.02). In males, ADJ exposure also independently predicted lower CSM rates, but to greater extent (HR:0.68, P <
0.001). CONCLUSION: Although both male and female patients benefit of improved survival with either NAC or ADJ, the magnitude of this benefit is significantly lower in female patients to that recorded in male counterparts.