INTRODUCTION AND HYPOTHESIS: The objective of our study was to evaluate the need for antibiotic prophylaxis for urinary tract infection (UTI) prevention before Onabotulinum toxin A injection for overactive bladder (OAB). We hypothesize that the lack of antibiotic prophylaxis might not be inferior to administering prophylaxis. METHODS: This was a multi-centered, nonblinded, randomized controlled trial conducted between August 2022 and September 2024. Participants were randomized to either receive oral antibiotics or no treatment. Our primary outcome was to measure the rate of UTI at 2 weeks. Our secondary outcomes included post-void residuals, assessment for antibiotic compliance, and UTI rates at 6 weeks. Given a 20% UTI rate and a delta of 20%, 64 participants per study arm were necessary to achieve 80% power with an alpha value of 0.05. RESULTS: Rates of UTI at 2 weeks post-procedure were 9.2% in the antibiotics group and 10.9% in the control group (p = 0.75). UTI rates 6 weeks post-procedure were 4.7% in the antibiotics group and 11.1% in the control group (p = 0.21). When analyzing variables such as age, race, body mass index, menopause status, vaginal estrogen use, or the rates of positive pre-procedure urine cultures, no factors proved to be predictors of developing a UTI at 2 weeks post-procedure. The urinary retention rate in our study was 0.8%. CONCLUSIONS: Rates of UTI were not significantly different between patients who obtained antibiotics prophylaxis and those who did not at 2 and 6 weeks following injection. Foregoing antibiotics prophylaxis in order to safeguard from the dangers of antimicrobial resistance may be considered in the treatment of OAB with Onabotulinum toxin A.