Background: In hemodialysis (HD) patients, the presence of Heart failure (HF) at the start of dialysis is a strong and independent predictor of short and long-term mortality, and its prevalence increases with declining kidney function and HD time. Left ventricular (LV) ejection fraction (EF) is widely used as a measure of systolic function. Reduced EF (<50%) is an important prognostic marker, however, less than 15% of End-stage Renal Disease (ESRD) patients have detectable systolic dysfunction and the EF is susceptible to loading conditions, which change dramatically during interdialytic intervals. Global Longitudinal Strain (GLS) derived by 2D Speckle-Tracking Echocardiography (STE) is an emerging technique for measuring more subtle disturbances in LV systolic function. Although ESRD patients have subclinical evidence of impaired strain but preserved EF, there is evidence that GLS is better in ESRD group receiving maintenance HD compared with moderate-advanced CKD patients. This systematic review will evaluate the evidence related to the incremental prognostic value of LV GLS by 2D-STE concerning mortality and cardiovascular (CV) events in ESRD patients. Methods: This protocol is reported according to the PRISMA-P guideline. The databases PubMed, EMBASE, LILACS, Web of Science, and Google Scholar system will be searched and double screening for longitudinal studies that assessed the prospective association of STE-derived parameters with at least one of the pre-specified outcomes in ESRD patients. Discrepancies will be resolved through consensus. A modified version of the Newcastle-Ottawa Quality Assessment Scale of cohort studies will be used. We intend to use the random-effects model, considering at least moderate heterogeneity between studies. If data allow, we will perform meta-regression to explore potential sources of between-study heterogeneity. An adaptation of the GRADE framework for prognostic studies will be employed to judge the quality of evidence for each outcome reported in this systematic review. Discussion: This systematic review will summarize current evidence about STE-derived measures in ESRD patients and clarify the incremental prognostic value of this diagnostic tool versus LVEF in these patients. Evidence about other measures (circumferential and radial strain) or 3D STE-derived indices will also be investigated.