Resting ST segment depression has been identified as a marker for adverse cardiac events in patients with and without known coronary artery disease. To correlate this with exercise testing, coronary angiography, and how it impacts on long-term prognosis, a retrospective study was performed on 476 patients, of whom 223 had no clinical or electrocardiographic evidence of prior myocardial infarction while 253 were survivors of an infarction. All patients performed a standard exercise test and underwent diagnostic coronary angiography within an average of 32 days of their exercise test (range 0 to 90 days). Exclusions were women, those with left bundle branch block, left ventricular hypertrophy, use of digoxin, previous revascularization procedures, or significant valvular or congenital heart disease. Long-term follow-up was carried out for an average of 45 months (+/- 17). Of the patients without prior infarction, 23 (10%) had persistent resting ST segment depression, and of those with a prior history of infarction, 37 (15%) also had resting ST segment depression. Patients with resting ST segment depression and no prior myocardial infarction had a higher prevalence of severe coronary disease (three-vessel and/or left main) (30%) than those without resting ST segment depression (16%) (95% confidence interval [CI] for observed difference -5.0% to 33.9%, p = 0.12). The criterion of greater-than-or-equal-to 2 mm of additional exercise-induced ST segment depression was a particularly useful marker in these patients for the diagnosis of any coronary disease (likelihood ratio 3.35, 95% CI 0.56 to 19.93, p = 0.06). Patients with resting ST segment depression and a prior myocardial infarction had a 2.5 times higher prevalence of severe coronary artery disease compared with patients without resting ST segment depression (43% versus 17% prevalence, respectively, 95% CI for observed difference 9.38% to 42.8%, p < 0.001) and also had larger left ventricles postinfarction (left ventricular end-diastolic volume index 102 ml/m2 compared with 96 ml/m2, p < 0.001). To identify severe coronary artery disease in post-infarction patients with persistent resting ST segment depression, the criteria of greater-than-or-equal-to 2 mm of additional exercise-induced ST segment depression (likelihood ratio 2.96, 95% CI 1.12 to 7.92, p = 0.02) or having the additional exercise-induced ST segment depression persist greater-than-or-equal-to 4 minutes into recovery (likelihood ratio 3.62, 95% CI 1.41 to 9.27, p = 0.002) were better markers than the standard criterion of greater-than-or-equal-to 1 mm of additional ST segment depression (likelihood ratio 1.67, 95% CI 1.07 to 2.61, p = 0.02). Receiver operating characteristic curve analysis revealed that additional exercise-induced ST segment depression continued to discriminate between those with or those without any, or severe, coronary disease despite having baseline ST segment depression at rest (p less-than-or-equal-to 0.005). After a cumulative follow-up of 4.4 years, patients with resting ST segment depression, with (p = 0.079) or without (p = 0.009) prior myocardial infarction, had a lower infarct-free survival rate than those without it. Resting ST segment depression (not due to left ventricular hypertrophy, conduction defects, or drug effect) is a marker for a higher prevalence of severe coronary artery disease with a poor prognosis, and standard exercise testing continues to be diagnostically useful in these patients.