End Tidal CO2 (ETCO2) is a reasonable predictor of Return of Spontaneous Circulation (ROSC) in cardiac arrest (CA), though with many limitations. Cerebral Oximetry (CerOx) non-invasively measures brain O2 saturation and correlates with flow. This study compares ETCO2 and CerOx for ROSC prediction during both out of hospital (OHCA) and emergency department cardiac arrests (EDCA). We conducted a prospective study on CA patients resuscitated in the ED. ETCO2 and CerOx simultaneously measured during ED CPR. Data was analyzed with logistic regression modeling and area under the curve (AUC). 176 patients were analyzed, 66.7% were witnessed, 52.8% had bystander CPR. EMS alert to ED arrival was 27.0 ± 10.6 min. Initial rhythm was 31.8% asystole, 27.8% PEA, 25.6% VF/VT with 26.1% achieving ROSC. AUC predictors of ROSC were: last 5 min trend CerOx = 0.82 ; ETCO2 = 0.74, delta first to last CerOx = 0.86 ; ETCO2 = 0.73, the penultimate minute CerOx = 0.81 ; ETCO2 = 0.76, and final minute CerOx = 0.89 ; ETCO2 = 0.77. AUC comparison of simultaneous measurements (n = 125) revealed: last 5 min trend CerOx = 0.80 ; ETCO2 = 0.79, delta first to last CerOx = 0.83 ; ETCO2 = 0.75, penultimate minute CerOx = 0.83 ETCO2 = 0.74, and final minute CerOx = 0.89 ; ETCO2 = 0.75. Our data shows, both ETCO2 and rSO2 are good predictors of ROSC. We found CerOx superior to ETCO2 in predicting ROSC.