Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and α-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received α-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO2, end-tidal CO2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given α-chloralose compared with isoflurane exhibited a lower heart rate (63 ± 10 compared with 116 ± 15 bpm) and peripheral arterial pressure (52 ± 12 compared with 61 ± 12 mm Hg); higher SpO2 (98% ± 3% compared with 95% ± 1%), end-tidal CO2 (35 ± 4 compared with 32 ± 5), and systolic blood pressure (121 ± 8 compared with 104 ± 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 ± 0.50 compared with 1.23 ± 0.19) and troponin I mean values (0.09 ± 0.07 ng/mL compared with 0.09 ± 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for α-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with α-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of α-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE.