The cause and associated pathophysiology of precordial ST-segment depression (ST decreases) during acute inferior myocardial infarction (IMI) are controversial. To investigate this problem, electrocardiographic findings in 48 consecutive patients with acute IMI were prospectively compared with results of coronary angiography, submaximal exercise thallium-201 (201TI) scintigraphy and multigated blood pool imaging, all obtained 2 weeks after IMI, and with clinical follow-up at 3 months. Patients were classified according to the admission ECG obtained 3.3 +/- 3.1 hours after the onset of chest pain. Twenty-one patients (group A) had no or less than 1.0 mm ST decreases, and 27 (group B) had greater than or equal to 1.0 mm ST decreases in two or more precordial (V1-6) leads. Patients in group B had more prolonged chest pain after admission to the coronary care unit than those in group A (2.8 +/- 3.0 vs 1.2 +/- 1.1 hours, p less than 0.03), greater summed ST-segment elevation in leads II, III, aVF (6.7 +/- 4.7 vs 3.3 +/- 4.5 mm, p less than 0.02), higher plasma peak creatine kinase levels (1133 +/- 781 vs 653 +/- 482 IU/l, p less than 0.01), a higher prevalence of "true posterior" infarction by ECG criteria (26% vs 5%, p less than 0.05), a lower radionuclide ejection fraction (46 +/- 9% vs 54 +/- 6%, p less than 0.001), more extensive infarct-related asynergy (p less than 0.001) and 201TI perfusion abnormalities (p less than 0.01), more complications during hospitalization (p less than 0.03), and more cardiac events at 3 months (p less than 0.02). There were no significant differences between group A and group B in the extent of underlying coronary disease, prevalence of left anterior descending coronary artery disease, exercise-induced ST decreases or angina, and 201TI defects or wall motion abnormalities in anterior or septal segments. Thus, patients with acute IMI who have associated precordial ST decreases have greater global and regional left ventricular dysfunction due to more extensive inferior or inferoposterior wall infarction, rather than concomitant anteroseptal ischemic injury.