The prognosis of patients with coronary artery disease (CAD) is mainly influenced by organic factors such as cardiac muscle loss and extent of CAD. The aim of this study was to investigate whether a functional factor--reversible myocardial ischemia at rest--plays an independent prognostic role. Thus, 2 groups of patients were studied and followed up for 46 +/- 32 months: 1 group (483 patients) had ischemic electrocardiographic changes only on effort and another group (224 patients) both on effort and at rest. The 2 groups did not differ significantly as to age, gender, coronary risk factors, baseline electrocardiographic abnormalities, incidence of previous myocardial infarction, angiographic left ventricular dysfunction, and extent of coronary stenoses (> or = 50% diameter reduction). There were 65 deaths (40 of which were from cardiac causes) during the 5-year follow-up. Despite the similar incidence of known predictors of prognosis, Kaplan-Meier survival analysis revealed a significantly lower 5-year survival rate in patients with mixed (84.4%) rather than exertional (92.1%) ischemia (p < 0.05 by Mantel-Haenszel test). If only cardiac causes of deaths were considered, the 5-year survival rate was still lower in patients with mixed (89.6%) rather than exertional (93.9%) ischemia. Finally, reversible ischemia at rest was an independent predictor of survival by Cox multivariate regression analysis, preceded only by the extent of CAD and left ventricular dysfunction. Thus, reversible ischemia at rest plays an independent negative role in the long-term clinical outcome of patients with CAD and positive exercise stress test results.