Background: Mental stress induced myocardial ischemia (MSIMI) is linked to increased risk of adverse cardiovascular outcomes, but its mechanisms are thought to be different from those of conventional stress-induced ischemia (CSIMI). Specifically, whether MSIMI is associated with more severe underlying obstructive coronary artery disease (CAD) is unclear. We investigated the association between angiographically-defined CAD severity and both MSIMI and CSIMI with a hypothesis that, CAD severity will be linked to CSIMI, but not MSIMI. Methods: A total of 273 patients with stable CAD, aged 51±7 years, 49% female, who survived a myocardial infarction (MI) within the past 8 months (median 167±52 days) were enrolled in the Myocardial Infarction and Mental Stress 2 (MIMS-2) study. The coronary angiogram performed during the index MI hospitalization was used to assess CAD severity. Coronary artery obstruction was assessed by counting the number of diseased vessels with 70% stenosis (DV70%) and using the Gensini Score (GS) after correcting for revascularized vessels. Patients underwent 99mTc sestamibi myocardial perfusion imaging during mental stress, using a public speaking task, and during conventional stress test, using exercise or pharmacological stress. MSIMI and CSIMI were defined as a new or worsening impairment in myocardial perfusion using a 17-segment model. Results: A total of 68 (26%) patients developed CSIMI, while 46 (17%) developed MSIMI. Median DV70% and GS were 0 (0-1), and 3 (0-12), respectively. Using logistic regression models, and after adjustment for age, gender, hypertension, hyperlipidemia and diabetes, obstructive CAD was associated with increased risk of CSIMI [OR(95%CI) of 1.54 (1.02 - 2.31) for DV70% and 1.25 (1.03-1.53), for GS], but not MSIMI [OR(95%CI) of 0.93 (0.56 - 1.53) for DV70%, and 0.94 (0.75-1.18) for GS]. Conclusion: Although CSIMI is linked to underlying coronary obstruction, MSIMI is independent of CAD severity among post- MI patients. Other mechanisms are likely responsible for MSIMI post MI.