Background: Adding an impedance threshold device (ITD) to active compression decompression CPR (ACD-CPR) has been shown to significantly improve long-term survival with favorable neurologic outcome following out-of-hospital cardiac arrest (OOHCA) of cardiac etiology. We hypothesized that ITD+ACDCPR would also increase survival with good neurologic function from all non-traumatic etiologies compared to standard CPR (SCPR). Methods: This prospective, randomized trial evaluated adults with OOHCA in seven US study sites. Patients were randomized to ITD+ACD-CPR or S-CPR on a 1:1 proportional basis. CPR was initiated by the first arriving EMS provider. A run-in phase preceded the pivotal phase to assure study logistics were well-coordinated. A pre-planned analysis was conducted on data from all non-traumatic arrest patients with known outcomes, prospectively randomized into the run-in and pivotal phases (combined), on an intention-to-treat basis. The primary endpoint was survival to hospital discharge (HD) with good neurologic function, defined as a modified Rankin Score (MRS) .3; and at one year, a Cerebral Performance Category (CPC) score .2. Statistical analysis was performed using a 2-sided Fischer's Exact Test. Results: Both groups had similar clinical profiles, baseline demographics and resuscitative efforts. Survival to HD with MRS .3 was achieved in 5.69% (75/1318) in the S-CPR group, and 7.88% (110/1396) 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 .2 was achieved in 4.71% (61/1296) in the S-CPR group, and 6.38% (86/1349) in the ITD+ACDCPR group, p= 0.062 [Odds ratio=1.38 (95% confidence interval= 0.97,1.96)]. Conclusion: Compared to 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 (not significant). These findings support the use of ITD+ACD-CPR for treatment of adults with OOHCA from a variety of non-traumatic etiologies.