Many studies have demonstrated the prevalence of depression in patients with coronary artery disease (CAD), but few have examined this relation in those with chest pain who do not have obstructive CAD on angiography. The aim of this study was to compare the prevalence of depression amongst patients with chest pain in the presence or absence of obstructive CAD and a healthy control group without chest pain. This prospectively designed, observational cohort study used 2 independent data sets: (1) The Queen Elizabeth Hospital Coronary Angiogram Database (n = 1,144), consisting of 819 patients with obstructive CAD and 325 patients with nonobstructive CAD (NoCAD), all of whom had chest pain and (2) the North West Adelaide Health Study (NWAHS; n = 3,168), a population-based biomedical cohort, from which patients with chest pain were excluded. The presence of depression was determined by a previously validated method using the Short Form 36. The prevalence of depression differed among the 3 groups, with 63% in those with NoCAD, 53% in those with CAD, and only 24% in the healthy NWAHS cohort. Analysis of the angiography cohort revealed age, gender, antidepressant medication, previous myocardial infarction, previous airway disease, Short Form 36 physical summary score, Seattle Angina Questionnaire physical limitation score, and NoCAD on angiography to be independent predictors of depression. In conclusion, these findings highlight the importance of screening for depression in patients with NoCAD.