Routinely, the thermodilution (TD) method was employed to estimate cardiac output (Q̇C). In contrast to the gold-standard Fick method, where systemic oxygen uptake (V̇O2) was directly measured, Q̇C was calculated from V̇O2, and the arterio-venous oxygen difference (“direct” Fick), this approach’s accuracy was not adequately demonstrated. The study compared the TD and Fick methods in consecutive patients who underwent pulmonary artery catheterization for various clinical problems. It was a subanalysis of a prior study that compared the indirect versus Fick method in 253 individuals who underwent pulmonary artery catheterization for clinical indications at a single center between 1999 and 2005. Researchers included patients whose Q̇C was estimated using the Fick approach with measured V̇O2 from breathed gas analysis in timed Douglas bag collections and the TD method. The cardiac index was categorized as poor when less than or equal to 2.2 L/min/m2 and normal when more than 2.2 L/min/m2. The cohort’s median (25th, 75th percentile) age was 59 (50,67), and 50% of the cohort was female. Ventriculography revealed that 43.5% had a normal left ventricular function, while 25.7% had ischemic heart disease. (p=0.04) The overall median Fick and TD Q̇C were 4.4 (3.5, 5.5) and 4.3 (3.7, 5.2) L/min, respectively. The median absolute percent error between Fick and TD Q̇C was 17.5% (7.7%, 28.4)%, with an average error of 0.88 L/min (95% CI 0.82 to 0.95). The median absolute percent error was comparable for the low (n=118) and normal (n=135) Q̇CI groups (P=0.88; 16.9% vs 18.9%, respectively). In this comparison, the mean error was 0.3 (95% CI 0.27 to 0.33) and 0.49 (95% CI 0.45 to 0.55) L/min/m2. Over 30% of patients exhibited a percent error of more than 25% between Fick and TD Q̇C. Overall, Fick and TD Q̇C were moderately correlated (Rs=0.64, P<0.001), with TD Q̇C introducing a nondirectional error [mean bias of 0.21 (−2.2, 2.7) L/min]. The poor agreement between TD and the gold-standard Fick technique demonstrated the limitations of using TD to make clinical choices.