INTRODUCTION: The investigational vaginal pH regulator (VPRTM) is a non-hormonal, woman-controlled contraceptive vaginal gel. The objectives of the current analysis are to report on genitourinary (GU) side effects with VPR based on the phase 3 AMPOWER trial. METHODS: AMPOWER was a single-arm, open-label, IRB-approved, multi-center trial based in the United States (NCT03243305). Women, aged 18-35 years, administered VPR intravaginally up to 1 hour before each episode of vaginal intercourse. The primary study objective was contraceptive efficacy over 7 cycles of use. Safety was assessed through adverse event reporting. RESULTS: In 1,330 women included in the safety analysis, the most common adverse events (10% or greater) were vaginal burning (20.0%) and itching (11.2%). Rates of vaginal burning and itching generally decreased over time (burning: Cycle 0=11.2%, Cycle 3=4.2%, Cycle 7=1.4%; itching: 4.5%, 1.1%, and 0.3%, respectively). Rates of burning and itching by act of intercourse were lower when VPR was used once/day (2.1% and 0.7%, respectively) compared to 2 or more times/day (4.6% and 1.0%, respectively). In women who had GU infections on-study (n=77), rates of burning (32.5%) and itching (22.1%) were higher than in the general study population. Women with a history of bacterial vaginosis (n=245) had similar rates of burning (21.6%) and itching (12.7%) compared to the general study population. Overall, 1% [13/1330] of women discontinued due to GU symptoms. CONCLUSION: In the phase 3 AMPOWER trial, rates of GU symptoms with VPR decreased substantially over time, with higher rates reported in women with existing GU infections compared to the general study population.