Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.