Background: Transurethral resection of bladder tumor (TURBT), chemotherapy (CT), and radiation therapy (RT) is an established treatment paradigm for muscle-invasive bladder cancer (MIBC). Herein we report long-term outcomes for MIBC patients treated with combined-modality therapy (CMT). Methods: We analyzed 465 patients with MIBC (cT2-T4a) treated on successive protocols at a single center between 1986 and 2012. Patients underwent TURBT followed by concurrent cisplatin-based chemoradiation (CRT). A subset of patients received neoadjuvant CT. Repeat cystoscopy was performed after 40 Gy. Patients with a complete response (CR) received consolidation CRT to 64-65 Gy, while those with less than a CR or invasive recurrence were recommended to undergo salvage RC. Overall survival (OS) and disease-specific survival (DSS) were evaluated using Kaplan-Meier method and Cox proportional hazards regression. Results: Median follow-up was 4.8 years for all patients and 7.5 years for surviving patients. CR to induction CRT was achieved in 76% patients; 84% of patients with a complete TURBT achieved a CR vs. 59% with an incomplete TURBT, p< 0.001. When evaluated in four-year intervals, the CR rate improved from 64% in 1986-1990 to 96% in 2010-2012. Salvage RC was performed in 125 patients (27%), 55 for less than CR and 70 for superficial or invasive recurrence. Among patients with a CR, the 10-year actuarial rates for non-invasive, invasive, pelvic, and distant failure were 32%, 16%, 14%, and 29%, respectively. Median OS was 6.4 years. Five- and 10-year OS rates were 57% and 39% (T2 = 66%, 46%; T3-T4a = 41%, 26%), respectively. Five- and 10-year DSS rates were 66% and 59% (T2 = 75%, 66%; T3-T4a = 50%, 45%), respectively. In multivariate analyses, T2 disease (vs. T3-4; HR 0.55, 95%CI 0.40-0.76) and CR to induction therapy (HR 0.40, 95%CI 0.28-0.55) were significant predictors for improved OS. Age was not associated with DSS (HR 1.01, 95%CI 0.99-1.03). Conclusions: These data support the high rates of CR and bladder preservation in patients receiving CMT, and demonstrate long-term DSS similar to modern cystectomy series. CMT should be considered as an alternative treatment strategy for selected patients with MIBC.