Measuring cardiac output is used to guide treatment during postresuscitation care. The aim of this study was to compare Doppler echocardiography (Doppler-CO) with thermodilution using pulmonary artery catheters (PAC-CO) for cardiac output estimation in a large cohort of comatose out-of-hospital cardiac arrest (OHCA) patients undergoing targeted temperature management (TTM). Single-center substudy of 141 patients included in the TTM trial randomly assigned to 33 or 36°C for 24 hours after OHCA. Per protocol, PAC-CO and Doppler-CO were measured simultaneously shortly after admission and again at 24 and 48 hours. Linear correlation was assessed between methods and positive predictive value (PPV) and negative predictive value (NPV) of Doppler to estimate low cardiac output (<3.5 L/min) was calculated. A total of 301 paired cardiac output measurements were available. Average cardiac output was 5.28 ± 1.94 L/min measured by thermodilution and 4.06 ± 1.49 L/min measured by Doppler with a mean bias of 1.22 L/min (limits of agreements-1.92 to 4.36 L/min). Correlation between methods was moderate (R2 = 0.36). Using PAC-CO as the gold standard, PPV of a low cardiac output measurement (<3.5 L/min) by Doppler was 33%. However, the NPV was 92%. Hypothermia at 33°C did not negatively affect the correlations of CO methods. In the lowest quartile of Doppler, 13% had elevated lactate (>2 mmol/L). In the lowest quartile of thermodilution, 36% had elevated lactate (>2 mmol/L). In ventilated OHCA patients, the two methods for estimating cardiac output correlated moderately and there was a consistent underestimation of Doppler-CO. Absolute cardiac output values from Doppler-CO should be interpreted with caution. However, Doppler can be used to exclude low cardiac output with high accuracy. TTM at 33°C did not negatively affect the correlation or bias of cardiac output measurements. ClinicalTrials.gov ID: NCT01020916.