Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemo or decline it. Adjuvant radiotherapy (RT) is an alternative (or complementary) adjuvant therapy, but is rarely performed, with most of these patients being observed. In a prospective trial, we compared RT vs adjuvant chemo & hypothesized that RT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial at the National Cancer Institute (Cairo) compared adjuvant RT (standard of care in Egypt) vs. chemo+RT after RC for LABC. A 3rd arm, adjuvant chemo, was added later (gemcitabine/cisplatin x 4). Herein, we report results of RT vs adjuvant chemo. Patients ≤70 y/o with ≥1 of the following (pT3b/T4a, grade 3 or pN+) with negative margins after RC were eligible. RT was delivered with 3-D conformal RT to the pelvis (45 Gy in 1.5 Gy BID). Routine follow-up & pelvic CT q 6 months were performed. Post hoc non-inferiority exploratory analysis was performed. Results: 123 were enrolled (78 RT/45 chemo). 51% had urothelial carcinoma; 49% had squamous cell carcinoma. The arms were well-balanced except for gender (p=0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for RT vs chemo were 54% vs 47% for DFS [HR 0.65(95%CI 0.35-1.19, p=0.16]; 92% vs 69% for local-regional recurrence-free survival [HR 0.28(95%CI 0.10-0.82), p=0.02]; 75% vs 79% for distant metastasis-free survival [HR 2.39(95%CI 0.94-6.09), p=0.07]; 61% vs 60% for overall survival [HR 0.94(95%CI 0.52-1.69), p=0.83]. In the urothelial cohort, there were no differences in DFS or OS. Late grade ≥3 GI toxicity was observed in 6 RT patients (8%) & 1 chemo patient (2%). Based on our data, there is a >90% probability that the true difference in 2-year DFS is <10%, the prespecified non-inferiority margin. Conclusions: This prospective study demonstrates that adjuvant RT has superior local control vs adjuvant chemo with no statistically significant differences in DFS or OS. Results suggest that RT can be an option for patients with LABC after RC where an alternative to chemo is desired by the patient or physician. Clinical trial information: NCT01734798