This study investigated both the in-hospital and long-term prognostic significance of ST-segment depression in non-infarct-related leads in patients who received thrombolytic therapy after acute myocardial infarction (AMI). We evaluated 221 consecutive patients who were admitted with their first AMI and underwent thrombolysis. Patients were followed for an average of 31 months and were classified into 3 groups: group 1 included 51 patients with persistent ST-segment depression, group 2 had 97 patients with transient ST-segment depression, and group 3 consisted of 73 patients without ST-segment depression (absent). Group 1 had significantly worse long-term survival during follow up by Kaplan-Meier analysis (55%) versus group 2 (81%) and group 3 (94%) (p = 0.0004) and higher event rates. This prognostic significance seemed to be maintained in both the anterior and inferior wall AMI groups. Multivariate analysis, using the Cox model, showed that Killip class, in-hospital left ventricular ejection fraction, and the persistence of ST-segment depression on the predischarge electrocardiogram (group 1) were independent predictors of survival. ST-segment depression in non-infarct-related leads on the predischarge electrocardiogram is an independent risk factor for worse long-term survival after anterior as well as inferior AMI treated with thrombolytic therapy.