The aim of this study was to ascertain if arterial waveform-derived cardiac output measurements from radial and femoral cannulation sites were reliable as compared with transesophageal echocardiography (TEE)-derived cardiac output (CO) values, and which of the CO measurements derived from radial and the femoral arterial pressure waveforms closely tracked simultaneously measured TEE-derived CO values. This study also aimed to ascertain if cardiopulmonary bypass (CPB) would impact the accuracy of arterial pressure-derived CO values from either of the 2 sites. A prospective observational study. Tertiary care cardiac center. Cardiac surgical patients undergoing on-pump primary coronary artery bypass surgery. Waveform-derived CO monitoring through radial and femoral artery cannulation using a FloTrac/Vigileo system. Twenty-seven consecutive cardiac surgical patients undergoing on-pump primary coronary artery bypass surgery were included in the study. Cardiac output was measured sequentially by the arterial pressure waveform analysis method from radial and femoral arterial sites and compared with simultaneously measured TEE-derived CO. Cardiac output data were obtained in triplicate at 6 predefined time intervals: before and after sternotomy, 5, 15, and 30 minutes after separation from CPB and prior to shifting the patient out of the operating room. The overall bias of the study was 0.11 and 0.27, the percentage error was 19.31 and 18.45, respectively, for radial and femoral arterial waveform-derived CO values as compared with TEE-derived CO measurements. The overall precision as compared with the TEE-derived CO values was 16.94 and 15.95 for the radial and femoral cannulation sites, respectively. The bias calculated by the Bland-Altman method suggested that CO measurements from the radial arterial site were in closer agreement with TEE-derived CO values at all time periods, and the relation was not affected by CPB. However, percentage error and precision calculations showed that CO values derived from the femoral arterial waveform were in closer agreement, albeit marginally, with the TEE values at all time points. Both the radial and femoral arterial pressure waveform-derived CO measurements were comparable with the TEE measurements during the various stages of the cardiac surgery. Although the femoral cannulation site provided marginally better correlation with the reference TEE-derived CO values based on the precision and percentage error analysis; this may not be significant clinically and either of the arterial cannulation sites can be used reliably for CO measurements in clinical practice. Cardiopulmonary bypass had no impact on the radial and femoral artery pressure waveform-derived CO measurements.