Acute myocardial infarction (AMI) is one of many causes of electrocardiographic ST segment elevation (STE) in ED chest pain (CP) patients; at times, the electrocardiographic diagnosis may be difficult. Coexistent ST segment depression has been reported to assist in the differentiation of non-infarction causes of STE from AMI-related ST segment elevation. The objective was to determine the effect of AMI diagnosis on the presence of STD among ED CP patients with electrocardiographic STE. Adult CP patients with electrocardiographic STE in at least 2 anatomically distributed leads were reviewed for the presence or absence of ST segment depression in at least 1 lead and separated into 2 groups, both with and without ST segment depression. A comparison of the 2 groups was performed in 2 approaches: all STE patients and then only with STE patients who lacked confounding electrocardiographic pattern (bundle branch block [BBB], left ventricular hypertrophy [LVH], or right ventricular paced rhythm [VPR]). All patients in the study underwent prolonged observation in the ED (at least 8 hours) with 3 serial troponin T determinations and 3 electrocardiograms (ECG). AMI was diagnosed by abnormal serum troponin T values (>0.1 mg/dL); electrocardiographic STE diagnoses of non-AMI causes were determined by medical record review. There were 171 CP patients with STE were entered in the study with 112 (65.5%) individuals show ST segment depression. When considering all study patients, ST segment depression was present at statistically equal rates in AMI and non-AMI situations (P = NS). The sensitivity, specificity, positive predictive value, and negative predictive value for the electrocardiographic diagnosis of AMI were 63%, 34%, 30%, and 67%, respectively. Patients with confounding patterns (LVH 46, BBB 19, and VPR 6) were removed from the analysis group, leaving 100 patients for analysis; 38 of these patients had ST segment depression. When considering this group of study patients, ST segment depression was present significantly more often in AMI patients (P <.0001). The sensitivity, specificity, positive predictive value, and negative predictive value for the electrocardiographic diagnosis of AMI were 69%, 93%, 93%, and 71%, respectively. Clinical diagnoses were as follows: 56 AMI, 50 USAP, and 65 noncoronary syndrome. When all CP patients with electrocardiographic STE are considered, the presence of ST segment depression is not helpful in distinguishing AMI from non-AMI. If one considers only patterns which lack electrocardiographic ST segment depression caused by altered intraventricular conduction, the presence of ST segment depression strongly suggests the diagnosis of AMI. In these cases, reciprocal ST segment depression is of considerable value in establishing the electrocardiographic diagnosis of STE AMI.