The aim of this study was to evaluate layer-specific global longitudinal strain (GLS), obtained by speckle tracking, in predicting outcomes following ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Echocardiography, including layer-specific GLS, was performed at median two days after the STEMI in a prospective study of STEMI patients treated with pPCI between September 2006 and December 2008. The outcome was the composite of heart failure hospitalization and/or cardiovascular death (HF/CVD). A total of 349 patients were included. Mean age was 62.2 ± 11.5 years, 76% were male, and mean ejection fraction (LVEF) was 46 ± 9. Seventy-seven (22%) patients developed HF/CVD during median follow-up 5.4 years. Patients with HF/CVD had lower absolute values for all GLS-layers: endocardial (GLSEndo) 11.4%vs 14.5% (p < 0.001), midmyocardial (GLSMid) 9.8% vs 12.5% (p < 0.001) and epicardial (GLSEpi) 8.5% vs 10.9% (p < 0.001). In unadjusted analysis, all layers were significant predictors of HF/CVD; hazard ratio (HR) per 1% decrease for GLSEndo: HR 1.18 (95%CI 1.11–1.25), GLSMid: HR 1.22 (95%CI 1.14–1.30) and GLSEpi: HR 1.26 (95%CI 1.16–1.36), p < 0.0001 for all. The risk of HF/CVD increased incrementally with increasing tertiles for all layers, being more than three times higher in 3rd tertile compared to 1st tertile. In multivariable models, including baseline clinical and echocardiographic parameters, only GLSMid and GLSEpi remained independent predictors of HF/CVD. Global longitudinal strain obtained from all myocardial layers were significant predictors of incident HF and CVD following STEMI, however, only GLSMid and GLSEpi remained independent predictors after multivariable adjustment.