OBJECTIVES To determine the effects of oxybutynin chloride topical gel (OTG), a novel 10% ethanolic formulation, on health-related quality of life (HRQoL) in adults with overactive bladder (OAB). METHODS Women and men aged ≥18 years with urge urinary incontinence were enrolled at 76 centers in a randomized, double-blind, placebo-controlled, parallel-group study (00350636 at clinicaltrials.gov). Patients applied 1 g OTG once daily or matching placebo gel for up to 12 weeks. To assess HRQoL, investigators asked patients to complete 2 disease-specific questionnaires (Incontinence Impact Questionnaire [IIQ]; King's Health Questionnaire [KHQ]) at baseline and weeks 1, 4, 8, and 12. Effects of OTG on HRQoL were assessed by computing mean change in questionnaire scores from baseline to week 12 or last observation. Differences between active and placebo treatment were compared by analysis of covariance. RESULTS In this study completed May 2007, 704 women and 85 men were enrolled; 389 patients received OTG and 400 received placebo. IIQ total score improved significantly more in patients treated with OTG (mean change, -72.1 points; P=.0005) than in those receiving placebo (mean change, -49.5 points). OTG also improved HRQoL significantly more (P≤.0078) than did placebo in all 4 IIQ subscales (Travel, Physical Activity, Social Relationships, and Emotional Health). Mean KHQ scores improved significantly more (P≤.0489) with OTG than with placebo in 6 of 10 domains, many directly associated with OAB symptoms (Incontinence Impact, Symptom Severity, Role Limitations, Personal Relationships, Sleep/Energy, and Severity [Coping] Measures). Dry mouth was the most common treatment-related adverse event in patients given OTG (27/389; 6.9%), but was not a primary reason for any patient to stop treatment. CONCLUSIONS OTG treatment significantly improved HRQoL in adults with OAB.