In the post-myocardial infarction phase, mortality risk is related to the severity of mitral regurgitation (MR). Ischemic MR is a dynamic condition that can be studied during exercise. Whether the assessment of exercise-induced changes in the degree of MR provides prognostic information is unknown. Ninety-eight consecutive patients with chronic ischemic left ventricular dysfunction and at least mild MR who prospectively underwent quantitative measurement of the regurgitant volume and the effective regurgitant orifice (ERO) of MR at rest and during semisupine exercise test were followed up for 19+/-8 months. The 16 patients who underwent surgery were censored at the time of operation. Of the 82 patients who were medically treated, 9 (11%) died. No clinical data demonstrated a distinction between survivors and nonsurvivors. By multivariate Cox regression analysis, independent predictors of cardiac death were an increase in ERO by > or =13 mm2 (P=0.0045) during exercise, an ERO >20 mm2 at rest (P=0.01), and a shorter mitral deceleration time (P=0.044). Half of the patients with exercise-induced significant increases in MR who died had moderate MR at rest. In contrast, none of the 14 patients with a decrease in MR at exercise displayed cardiac death. In patients with ischemic MR and left ventricular dysfunction, quantitative assessment of exercise-induced changes in the degree of MR provides independent prognostic information. Significant exercise-induced increases in MR unmask patients at high risk of poor outcome.