Background: To compare continuous cardiac output obtained by simulation of an aortic input impedance model to bolus injection thermodilution (TDCO) in critically ill patients with septic shock. Methods: In an open study, mechanically ventilated patients with septic shock were monitored for 1 (32 patients), 2 (15 patients), or 3 (5 patients) days. The hemodynamic state was altered by varying the dosages of dopamine, norepinephrine, or dobutamine. TDCO was estimated 189 times as the series average of four automated phase-controlled injections of iced 5% glucose, spread equally over the ventilatory cycle. Continuous model-simulated cardiac output (MCO) was computed from radial or femoral artery pressure. On each day, the first TDCO value was used to calibrate the model. Results: TDCO ranged from 4.1 to 18.2 l/min. The bias (mean difference between MCO and TDCO) on the first day before calibration was -1.92 +/- 2.3 l/min (mean +/- SD; n = 32; 95% limits of agreement, -6.5 to 2.6 l/min). The bias increased at higher levels of cardiac output (P <0.05). In 15 patients studied on two consecutive days, the precalibration ratio TDCO:MCO on day 1 was 1.39 +/- 0.28 (mean +/- SD) and did not change on day 2 (1.39 +/- 0.34). After calibration, the bias was -0.1 +/- 0.8 l/min with 82% of the comparisons (n = 112) <1 l/min and 58% (n = 79) <0.5 l/min, and independent of the level of cardiac output. Conclusions: In mechanically ventilated patients with septic shock, changes in bolus TDCO are reflected by calibrated MCO over a range of cardiac output values. A single calibration of the model appears sufficient to monitor continuous cardiac output over a 2-day period with a bias of -0.1 +/- 0.8 l/min.