Multilayer (epi-, mid- and endocardium) left ventricular (LV) global longitudinal strain (GLS) reflects the extent of myocardial damage after ST-segment myocardial infarction (STEMI). However, the prognostic implications of multilayer LV GLS remain unclear. We studied the association between multilayer LV GLS and prognosis in patients with mildly reduced or preserved LV ejection fraction (EF) after STEMI. Patients with first STEMI and LVEF>45% were evaluated retrospectively. Baseline multilayer (endocardial, mid-myocardial and epicardial) LV GLS were measured on 2-dimensional speckle tracking echocardiography. Patients were followed up for of all-cause mortality. A total of 569 patients (77% male, 60 ± 11 years) were included. After a median follow-up of 117 (interquartile range 106-132) months, 95 (17%) patients died. We observed no differences in baseline LVEF and peak troponin levels between survivors and non-survivors. However, non-survivors showed more impaired GLS at all layers (epicardium: -11.9 ± 2.8% vs. -13.4 ± 2.8%; mid-myocardium: -14.2 ± 3.2% vs. -15.6 ± 3.2%; endocardium: -16.5 ± 3.7% vs. -17.7 ± 3.6%, p <0.05, for all). On multivariable analysis, increasing age (hazard ratio 1.095; p<0.001) and impaired LV GLS of the epicardial layer (hazard ratio 1.085; p = 0.047) were independently associated with higher risk of all-cause mortality. In addition, LV GLS at the epicardium had incremental prognostic value for all-cause mortality (χ² = 114, p = 0.044). In conclusion, in contemporary STEMI patients with mildly reduced or preserved LVEF, ageing and reduced LV GLS of the epicardium (reflecting transmural scar formation) were independently associated with all-cause mortality after adjusting for clinical and echocardiographic variables.