Recent thoracic artificial lung (TAL) prototypes have impedances lower than the natural lung. With these devices, proximal pulmonary artery to distal pulmonary artery (PA-PA) TAL attachment may be possible in patients without right ventricular dysfunction. This study examined the relationship between pulmonary system impedance and cardiac output (CO) to create TAL design constraints. A circuit with adjustable resistance and compliance (C) was attached in a PA-PA fashion with the pulmonary circulation of seven sheep with chronic pulmonary hypertension. The pulmonary system zeroth harmonic impedance modulus (Z0) was increased by 1, 2.5, and 4 mmHg/(L/min) above baseline. At each Z0, C was set to 0, 0.34, and 2.1 mL/mmHg. The change in pulmonary system zeroth and first harmonic impedance moduli (ΔZ0 and ΔZ1), the percent change in CO (%ΔCO), and the inlet and outlet anastomoses resistances were calculated for each situation. Results indicate that ΔZ0 (p < 0.001) but not ΔZ1 (p = 0.5) had a significant effect on %ΔCO and that %ΔCO = -7.45*ΔZ0 (R2 = 0.57). Inlet and outlet anastomoses resistances averaged 0.77±0.16 and 0.10±0.19 mmHg/(L/min), respectively, and the relationship between %ΔCO and TAL resistance, RT, in mmHg/(L/min) was determined to be %ΔCO = -(7.45f)*(RT + 0.87), in which f = the fraction of CO through the TAL. Thus, newer TAL designs can limit %ΔCO to less than 10% if f < 0.75.