Aims To investigate the prognostic value of layer-specific global longitudinal strain (GLS) in predicting heart failure (HF) and cardiovascular death (CD) following acute coronary syndrome (ACS). Methods In this retrospective study, 465 ACS patients underwent transthoracic echocardiography following percutaneous and results coronary intervention (PCI). The primary endpoint was the composite of HF and/or CD with a median follow-up time of 4.6 (0.2–6.3) years. During follow-up 199 patients (42.7%) suffered HF and/or CD (176 developed HF and 38 suffered CD). Absolute endomyocardial global longitudinal strain (GLSendo) (12% vs. 17%, P < 0.001), GLS (11% vs. 14%, P < 0.001), and epimyocardial global longitudinal strain (GLSepi) (9% vs. 13%, P < 0.001) were all reduced in patients with an adverse outcome. In multivariable Cox regressions, which included clinical baseline characteristics and conventional echocardiographic measurements, GLS obtained from all layers remained independently associated with the composite outcome; GLSendo [hazard ratio: 1.19 (1.10–1.28), P < 0.001, per 1% decrease], GLS [hazard ratio 1.24 (1.14–1.35), P < 0.001, per 1% decrease], and GLSepi [hazard ratio 1.26 (1.15–1.39), P < 0.001, per 1% decrease]. No other echocardiographic measures remained independently associated with the composite outcome in these models. Finally, GLS and GLSepi provided incremental prognostic information on the risk of developing the composite endpoint, when added to all other clinical and echocardiographic measures [adding GLS (c-statistics: 0.76 vs. 0.74, P = 0.048) or adding GLSepi (c-statistics: 0.76 vs. 0.74, P = 0.039)]. Conclusion In ACS patients, layer-specific strain provides independent prognostic information regarding risk of developing HF and/or CD. Furthermore, only GLS and GLSepi provided incremental prognostic information when added to all other significant predictors.