AIM: The objectives were: 1) replicate key elements of Head Up (HUP) cardiopulmonary resuscitation (CPR) physiology in a traditional swine model of ventricular fibrillation (VF), 2) compare HUP CPR physiology in pig cadavers (PC) to the VF model 3) develop a new human cadaver (HC) CPR model, and 4) assess HUP CPR in HC. METHODS: Nine female pigs were intubated, and anesthetized. Venous, arterial, and intracranial access were obtained. After 6min of VF, CPR was performed for 2min epochs as follows: Standard (S)-CPR supine (SUP), Active compression decompression (ACD) CPR+impedance threshold device (ITD-16) CPR SUP, then ACD+ITD HUP CPR. The same sequence was performed in PC 3h later. In 9 HC, similar vascular and intracranial access were obtained and CPR performed for 1min epochs using the same sequence as above. RESULTS: The mean cerebral perfusion pressure (CerPP, mmHg) was 14.5+/-6 for ACD+ITD SUP and 28.7+/-10 for ACD+ITD HUP (p=.007) in VF, -3.6+/-5 for ACD+ITD SUP and 7.8+/-9 for ACD+ITD HUP (p=.007) in PC, and 1.3+/-4 for ACD+ITD SUP and 11.3+/-5 for ACD+ITD HUP (p=.007) in HC. Mean systolic and diastolic intracranial pressures (ICP) (mmHg) were significantly lower in the ACD+ITD HUP group versus the ACD+ITD SUP group in all three CPR models. CONCLUSION: HUP CPR decreased ICP while increasing CerPP in pigs in VF as well as in PC and HC CPR models. This first-time demonstration of HUP CPR physiology in humans provides important implications for future resuscitation research and treatment.