OBJECTIVES: A rapid, ice-cold saline flush combined with active compression-decompression (ACD) plus an inspiratory impedance threshold device (ITD) cardiopulmonary resusitation (CPR) will cool brain tissue more effectively than with standard CPR (S-CPR) during cardiac arrest (CA). BACKGROUND: Early institution of hypothermia after CPR and return of spontaneous circulation improves survival and outcomes after CA in humans. METHODS: Ventricular fibrillation (VF) was induced for 8 min in anesthetized and tracheally intubated pigs. Pigs were randomized to receive either ACD + ITD CPR (n = 8) or S-CPR (n = 8). After 2 min of CPR, 30 ml/kg ice-cold saline (3°C) was infused over the next 3 min of CPR via femoral vein followed by up to three defibrillation attempts (150 J, biphasic). If VF persisted, epinephrine (40 μg/kg) and vasopressin (0.3 U/kg) were administered followed by three additional defibrillation attempts. Hemodynamic variables and temperatures were continuously recorded. RESULTS: All ACD + ITD CPR pigs (8 of 8) survived (defined as 15 min of return of spontaneous circulation [ROSC]) versus 3 of 8 pigs with S-CPR (p < 0.05). In survivors, brain temperature (°C) measured at 2-cm depth in brain cortex 1 min after ROSC decreased from 37.6 ± 0.2 to 35.8 ± 0.3 in ACD + ITD CPR versus 37.8 ± 0.2 to 37.3 ± 0.3 in S-CPR (p < 0.005). Immediately before defibrillation: 1) right atrial systolic/diastolic pressures (mm Hg) were lower (85 ± 19, 4 ± 1) in ACD + ITD CPR than S-CPR pigs (141 ± 12, 8 ± 3, p < 0.01); and 2) coronary perfusion pressures (mm Hg) were higher in ACD + ITD CPR (28.3 ± 2) than S-CPR pigs (17.4 ± 3, p < 0.01). CONCLUSIONS: A rapid ice-cold saline infusion combined with ACD + ITD CPR during cardiac arrest induces cerebral hypothermia more rapidly immediately after ROSC than with S-CPR.