Introduction. Active compression–decompression (ACD) cardiopulmonary resuscitation (CPR) plus augmentation of negative intrathoracic pressure with an impedance threshold device (ITD) has been shown to increase cerebral perfusion compared with standard CPR (S-CPR) by 1) increasing forward brain blood flow and 2) reducing resistance to brain flow by lowering intracranial pressure. The ResQ Trial compared ACD+ITD (n = 840 patients) vs. SCPR (n = 813) after out-of hospital, nontraumatic cardiac arrest of presumed cardiac etiology. ACD+ITD improved survival to hospital discharge, with favorable neurologic function by 53% (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.07–2.36; p = 0. 019). Because of differences in local practice, many of the patients in this trial were not treated with postresuscitation therapeutic hypothermia (TH), a neuroprotective therapy. Objective. The objective of this current analysis was to determine whether ACD+ITD is neuroprotective, independent of TH. Methods. Post hoc analysis of ResQ Trial data compared 1) the rate of hospital discharge with favorable neurologic function (modified Rankin score [MRS] <3) and 2) 90-day survivalwith favorable neurologic function (cerebral performance score [CPC] of <3) for all patients not treated with TH. Results. Without the use of TH, ACD+ITD was independently associated with a nearly twofold increase in the number of survivors with favorable neurologic function at the time of hospital discharge (ACD+ITD [40/711] vs. S-CPR [20/669], p = 0.017, odds ratio [OR] = 1.93, confidence interval [CI] = 1.09, 3.53) and 90 days after the cardiac arrest (ACD+ITD [35/706] vs. S CPR [19/664], p = 0.052, OR = 1.77, CI = 0.97, 3.31). Conclusion. In the absence of treatment with TH after cardiac arrest, survival rates with favorable neurologic function at hospital discharge and 90 days after cardiac arrest were nearly twice as high with ACD+ITD vs. S-CPR. These findings support the hypothesis that use of ACD+ITD is neuroprotective, independent of in-hospital TH.