Background: Urgency urinary incontinence (UUI) is a chronic condition for which sacral neuromodulation (SNM) (InterStim/Medtronic) and onabotulinumtoxinA (BTX) (BotoxA/Allergan) are utilized. These therapies have not been compared over extended time. Objective: To compare UUI episodes (UUIE) over 24 mo following SNM or BTX. Design, setting, and participants: Multicenter, open-label, randomized, extension trial (February 2012–July 2016) at nine US medical centers involving 386 women with ≥6 UUIE over 3 d inadequately managed by medications. Participants were clinical responders to treatment: ≥50% reduction in UUIEs after SNM placement or 1 mo post BTX. Intervention: SNM (n = 194) versus 200 U BTX (n = 192). SNM reprogrammings occurred throughout the 24 mo. After 6 mo, two additional BTX injections were allowed. Outcome measurements and statistical analysis: Primary outcome: change in mean daily UUIE over 24 mo. Secondary outcomes: no UUIE, ≥75% and ≥50% UUIE reduction; Overactive Bladder Questionnaire Short Form; Urinary Distress Inventory short form; Incontinence Impact Questionnaire; Patient Global Impression of Improvement; Overactive Bladder Satisfaction of Treatment Questionnaire; and adverse events (AEs). Primary analysis used a linear mixed model. Results and limitations: Outcome data were available for 260/298 (87%) clinical responders. No difference in decreased mean UUIE was found over 24 mo (−3.88 vs −3.50 episodes/d,95% confidence interval [CI] = −0.14–0.89; p = 0.15), with no differences in UUI resolution, ≥75% or ≥50% UUIE reduction. BTX group maintained higher satisfaction (mean difference = −9.14, 95% CI = −14.38–−3.90; p < 0.001), treatment endorsement (mean difference = −12.16, 95% CI = −17.7–−6.63; p < 0.001) through 24 mo. Other secondary measures did not differ. Recurrent urinary tract infections (UTIs) were higher after BTX (24% vs 10%; p < 0.01), 6% required intermittent catheterization post second injection. SNM revision and removals occurred in 3% and 9% patients, respectively. Conclusions: Both treatments offered sustainable UUI improvement, and higher BTX dosing had low clean intermittent catheterization rates, but with UTI risk. SNM revision/removal rates were low due to standardized lead placement with strict treatment response definitions. Patient summary: We compared a large group of US women with severe urgency urinary incontinence (UUI) who received sacral neuromodulation (InterStim) or onabotulinumtoxinA (Botox A) therapy during a 2-yr period. We found that both therapies had similar success in reducing UUI symptoms, and adverse events were low. However, women in the BotoxA group had higher satisfaction and endorsement with their treatment, but with a higher chance of a urinary tract infection. We conclude that both therapies offer sustained reduction in daily incontinence over 2 yr. Sacral neuromodulation and 200 U onabotulinumtoxinA resulted in similar sustained improvements in urgency urinary incontinence episodes throughout 24 mo. OnabotulinumtoxinA provided higher treatment satisfaction and endorsement, and greater treatment preference. Adverse events were low; however, urinary tract infection rates were higher following onbotulinumtoxinA.