Background: Little evidence guides the appropriate duration of resuscitation in out-of-hospital cardiac arrest, and case features justifying longer or shorter durations are ill defined. We estimated the impact of resuscitation duration on the probability of favorable functional outcome in out-of-hospital cardiac arrest using a large, multicenter cohort. Methods: This was a secondary analysis of a North American, single-blind, multicenter, cluster-randomized, clinical trial (ROC-PRIMED [Resuscitation Outcomes Consortium Prehospital Resuscitation Using an Impedance Valve and Early Versus Delayed]) of consecutive adults with nontraumatic, emergency medical services-treated out-of-hospital cardiac arrest. Primary exposure was duration of resuscitation in minutes (onset of professional resuscitation to return of spontaneous circulation [ROSC] or termination of resuscitation). Primary outcome was survival to hospital discharge with favorable outcome (modified Rankin scale [mRS] score of 0-3). Subjects were additionally classified as survival with unfavorable outcome (mRS score of 4-5), ROSC without survival (mRS score of 6), or without ROSC. Subject accrual was plotted as a function of resuscitation duration, and the dynamic probability of favorable outcome at discharge was estimated for the whole cohort and subgroups. Adjusted logistic regression models tested the association between resuscitation duration and survival with favorable outcome. Results: The primary cohort included 11 368 subjects (median age, 69 years [interquartile range, 56-81 years]; 7121 men [62.6%]). Of these, 4023 (35.4%) achieved ROSC, 1232 (10.8%) survived to hospital discharge, and 905 (8.0%) had an mRS score of 0 to 3 at discharge. Distribution of cardiopulmonary resuscitation duration differed by outcome (P<0.00001). For cardiopulmonary resuscitation duration up to 37.0 minutes (95% confidence interval, 34.9-40.9 minutes), 99% with an eventual mRS score of 0 to 3 at discharge achieved ROSC. The dynamic probability of an mRS score of 0 to 3 at discharge declined over elapsed resuscitation duration, but subjects with initial shockable cardiac rhythm, witnessed cardiac arrest, and bystander cardiopulmonary resuscitation were more likely to survive with favorable outcome after prolonged efforts (30-40 minutes). After adjustment for prehospital (odds ratio, 0.93; 95% confidence interval, 0.92-0.95) and inpatient (odds ratio, 0.97; 95% confidence interval, 0.95-0.99) covariates, resuscitation duration was associated with survival to discharge with an mRS score of 0 to 3. Conclusions: Shorter resuscitation duration was associated with likelihood of favorable outcome at hospital discharge. Subjects with favorable case features were more likely to survive prolonged resuscitation up to 47 minutes. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00394706.