Introduction. Adding an impedance threshold device (ITD) to active compression–decompression cardiopulmonary resuscitation (ACD-CPR) has previously been shown to significantly improve long-term survival with favorable neurologic outcome following out-of-hospital cardiac arrest (OOHCA) of cardiac etiology. Objective. We hypothesized that ITD+ACD-CPR would also increase survival with good neurologic function from all nontraumatic etiologies (e.g., presumed cardiac, overdose, stroke, metabolic imbalance, respiratory) compared with standard CPR (S-CPR). Methods. This prospective, randomized, multicenter trial evaluated adults (¡Ã18 years) with OOHCA in seven U.S. study sites (population 2.3 million). Patients were randomized to ITD+ACD-CPR (intervention) or S-CPR (control) on a 1:1 proportional basis. CPR was initiated by the first arriving basic life support (BLS) or advanced life support (ALS) emergency medical services (EMS) provider. A run-in phase preceded the pivotal phase to ensure that study logistics were well-coordinated. A preplanned analysis was conducted on data from all nontraumatic cardiac arrest patients with known outcomes, prospectively randomized and treated with either ITD+ACD-CPR or S-CPR from both the run-in and pivotal phases (combined) on an intention-to-treat basis. The primary endpoint was survival to hospital discharge with good neurologic function, which was defined as having a modified Rankin score (MRS) ¡Â3; and at one year, having a cerebral performance category (CPC) score ¡Â2. Statistical analysis was performed using a two-sided Fisher’s exact test. Results. The two groups had similar clinical profiles, baseline demographics, and resuscitative efforts. Survival to HD with MRS ¡Â3 was achieved in 5.69% (75/1,318) in the S-CPR group and 7.88% (110/1,396) in the ITD+ACD-CPR group, p = 0.027 (odds ratio = 1.42, 95% confidence interval 1.04, 1.95). Survival to one year with CPC ¡Â2 was achieved in 4.71% (61/1,296) in the S-CPR group and 6.38% (86/1,349) in the ITD+ACD-CPR group, p = 0.062 (odds ratio = 1.38, 95% confidence interval 0.97, 1.96). Conclusions. Compared with S-CPR, ITD+ACD-CPR resulted in a 38.5% increase in survival to hospital discharge with favorable neurologic function (p = 0.027) and a 35.4% increase in survival at one year with favorable neurologic function (NS). These findings support the use of ITD+ACD-CPR for the treatment of adults with OOHCA from a variety of nontraumatic etiologies.