Background: Neoadjuvant and adjuvant chemotherapy improve relapse-free survival (RFS) and overall survival of patients (pts) with MIBC. Limited information is available regarding risk prediction of local (RL) vs. distant relapse (RD), including role of perioperative chemotherapy (POC), added to radical cystectomy (Cy). Methods: Data from 1,559 pts, treated at 29 centers from the U.S., Europe, Israel, and Canada, were collected. Pts received Cy for MIBC from 02/90 to 12/13. Of these pts, 782 (50.2%) received POC and Cy, 777 (49.8%) Cy alone. RL and RD were defined as follows: pelvic lymph-nodes/soft tissue only and any extra-pelvic recurrences, respectively. Cumulative incidence methods were used to estimate time-to-(TT) RL/RD, which accounts for the competing risk of other types of relapse. Univariable and multivariable (MVA) Cox regression analyses were performed from the complete-case dataset (n = 1,082). Risk groups were defined according to the number of adverse factors, with corresponding nomogram-based RL and RD risk estimation. All tests were two-sided and statistical significance was defined as a p-value of 0.05 or less. Results: A total of 830 pts (55%) developed a relapse, 447 in the Cy group and 383 in the Cy+POC group. On MVA, POC administration was associated with longer TTRL (p < 0.001) and TTRD (p < 0.001). Other factors associated with RL: histology (non-UC, odds ratio [OR] = 1.47, 95%CI: 1.07-2.01, p = 0.022), pT-stage (p < 0.001), pN-stage (p = 0.038), surgical margins (p < 0.001). For RD: Charlson score (p = 0.006), pT-stage (p < 0.001), pN-stage (p < 0.001). The c-index of the model for RL was 0.685 (95% bootstrapped CI: 0.664-0.718), and for RD was 0.684 (0.655-0.721). Three risk group categories were obtained for both endpoints (0, 1-2, and > 2 risk factors). Results were confirmed after applying 90-day or 180-day landmark analyses, pending external validation. Conclusions: In the largest study that separately analyzed RL and RD risk, we were able to provide risk tools that may be used to optimize locoregional treatments and compare POC benchmark with new drugs in the perioperative setting.