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 (Z ART ) is an important physiologic determinant of left ventricular (LV) performance. We tested the hypothesis that Z ART is lower in bovine and porcine than in humans with normal or failing hearts.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 Z ART , and arterial resistance and compliance were estimated using a 4-element Windkessel model.Humans with HF had greater Z ART 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.Z ART 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.