Background: Advanced therapies for heart failure (HF), such as mechanical circulatory support (MCS) devices and xenotransplantation, are usually tested in bovine and porcine models. This approach assumes a priori that animal (patho)physiology will closely match that of humans. Systemic aortic input impedance (ZART) is an important physiologic determinant of left ventricular (LV) performance. We tested the hypothesis that ZART is lower in bovine and porcine than in humans with normal or failing hearts. Methods: High-fidelity aortic pressure and flow waveforms were recorded intra-operatively at native and paced heart rates of 100 beats per minute (bpm) in adult human patients with normal LV function (n = 13) or end-stage HF (n = 15), and normal calves (n = 10) and pigs (n = 18). Fast Fourier transformation was used to calculate ZART, and arterial resistance and compliance were estimated using a 4-element Windkessel model. Results: Humans with HF had greater ZART than those with normal LV function, characterized by higher resistance (1.16 ± 0.12 vs 1.00 ± 0.10 mm Hg · s/ml, p < 0.05) and lower compliance (1.53 ± 0.21 vs 1.88 ± 0.33 ml · mm Hg, p < 0.05). Healthy calves and pigs had significantly lower resistance (calf: 0.63 ± 0.07 mm Hg · s/ml; pig: 0.90 ± 0.07 mm Hg · s/ml) and higher compliance (calf: 2.79 ± 0.37 ml · mm Hg; pig: 2.80 ± 0.64 ml · mm Hg) when compared to humans (p < 0.05) with normal or failing hearts. Conclusions: ZART is significantly lower in calves and pigs than in humans with or without HF. This finding has important implications for the pre-clinical testing of MCS devices and xenotransplants, which are usually examined in bovine and porcine models, respectively. Specifically, these therapies may respond differently in humans than animals due to non-equivalence of systemic after-load. © 2008 International Society for Heart and Lung Transplantation.