Precordial ST-segment depression is typically observed in anterior non-0-wave acute myocardial infarction (AMI), and is generally not regarded as an indication for acute thrombolytic therapy. Of 544 patients with creatine kinase (CK)-MB-confirmed non-Q-wave AMI randomized to the prospective multicenter Diltiazem Reinfarction Study, 50 patients (9.2%) had isolated precordial ST-segment depression of 1 mm or more in 2 or more contiguous precordial electrocardiographic leads (V1-V4). Serial electrocardiograms recorded at study entry (mean 50.5 hours after onset of chest pain), on study day 2, study day 3 and at predischarge showed that in 23 of 50 patients (40%) electrocardiographic evidence of posterior AMI evolved, defined as an R wave of 0.04 second or more in lead V1 and an R:S ≥ 1 in lead V2. In 18 of these 23 patients (78%), posterior AMI had evolved by study day 3, and none had an abnormal reelevation of CK-MB (every 12-hour sampling) for up to 14 days of hospitalization. Compared with the remaining 27 patients who had electrocardiographic features of anterior non-Q-wave AMI only, the 23 with initial precordial ST-segment depression in whom posterior AMI developed had significantly higher mean peak CK values (1,051 ± 172 vs 663 ± 89 IU, p < 0.009) and greater mean precordial ST-segment depression in lead V1 (0.28 vs + 0.19 mm, p = 0.01), in lead V2 (1.3 vs 0.26 mm, p = 0.003) and in lead V3 (2.0 vs 0.93 mm, p = 0.0004). All 23 patients in whom posterior AMI evolved had horizontal ST-segment depression and upright precordial T waves, whereas all 27 patients with anterior non-Q-wave AMI had downsloping ST-segment depression with precordial T-wave Inversion. Thus, precordial ST-segment depression with upright T waves is an early electrocardiographic harbinger of posterior AMI and may initially masquerade as a non-Q-wave anterior AMI. Electrocardiographic progression to posterior AMI is generally manifest by day 3 in approximately 80% of patients, and is associated with larger CK increases at entry. The significance of early ST-segment depression in leads V1-V4 of an evolving AMI may signify ischemia of the posterior wall. Because the electrocardiographic "current of injury" for early posterior AMI is projected as reciprocal precordial ST-segment elevation, such patients should be considered eligible for early thrombolytic therapy.