Background: We have established that neoadjuvant (neo) chemotherapy (CTX) is the optimal strategy in localized SCUC given the frequent under staging. We have also demonstrated that alternating ifosfamide/doxorubicin (IA) and etoposide/cisplatin (EP) are active against SCUC; however, the optimal regimen has not been defined. Methods: We reviewed the records of 410 patients with SCUC treated at our institution between 1985 and 2020. Fisher’s exact test and logistic regression were used to determine the association between pathological complete response (pCR) and management approach. The Kaplan-Meier method was used to estimate overall survival (OS) from time of SCUC diagnosis to death or last follow up. Log rank test and Cox proportional models were used to determine the hazard-ratio (HR) between OS and management approach. Results: We included 203 patients with cT2-4aN0M0 SCUC who underwent cystectomy either after neoCTX (141, 69%), alone (38, 19%), or followed by adjuvant CTX (24, 12%). Clinical stage was cT2N0 (151, 74%), cT3/4N0 (44, 22%), or cTxN0 (8, 4%). Median age at diagnosis of SCUC was 66.7, 65.7, and 62.3 (p = 0.1) in the neoCTX, surgery alone and adjuvant CTX groups, respectively. Mean (+/- standard deviation) baseline glomerular filtration rate (GFR) was 75.6 (+/- 19.5), 61.3 (+/- 18.7), 70.5 (+/- 30.1) (p = 0.002) in the neoCTX, surgery alone and adjuvant CTX groups, respectively. Downstaging was significantly improved with neoCTX vs initial surgery (49.6% vs 14.5%, p <.0001), stage cT2N0 vs cT3/4N0 (44% vs 25%, p = 0.01), presence of carcinoma-in-situ (47% vs 28%, p = 0.01), or higher GFR (OR = 1.02, p = 0.06). In a multi-variable analysis of these factors, neoCTX was the only factor associated with pCR [OR = 3.9 (1.6-9.6) p = 0.003]. When comparing neoCTX regimens, downstaging was greatest with IA/EP (65%) as compared to EP (39%), MVAC/Gem/Cis (27%) or others (36%), p = 0.04. IA/EP was associated with younger age and good ECOG PS. In a multi-variable analysis of these factors, only IA/EP was associated with downstaging [OR = 3.7 (1.3-10.2), p = 0.01] and cT3/4 trended toward negatively impacting downstaging [OR = 0.5 (0.15-1.57), p = 0.23]. In the survival analysis, neoCTX, T2 vs T3/4, predominant small cell histology, good ECOG PS, higher GFR, and younger age were all significantly associated with improved outcomes. The best survival outcomes were observed with IA/EP (5-yr OS 64.2%), as compared to EP (5-yr OS 55.6%), MVAC/Gem/Cis (5-yr OS 50%) or others (5-yr OS 46.4%), p = 0.06, although these findings did not achieve statistical significance. Conclusions: NeoCTX remains the standard of care treatment for SCUC. The best downstaging was observed with IA/EP with a trend toward improved overall survival. We recommend the use of IA/EP whenever possible and consider EP for patients who are not able to tolerate ifosfamide.