Abstract Background Speckle tracking derived global longitudinal strain (GLS) could provide incremental prognostic information over left ventricular ejection fraction (LVEF) in the general population and a variety of cardiovascular diseases. Mitral annular systolic excursion (MAPSE) is a classical echocardiographic index with prognostic implication in patients with various cardiovascular diseases. Present study aimed to test the hypothesis that reduced GLS is superior to MAPSE on predicting all-cause mortality in non-ischemic heart failure patients with reduced ejection fraction. Methods A total of 952 patients with non-ischemic heart failure and reduced LVEF, who referred to our department between 2009 and 2017, were included in this study (mean age: 66±15 years, 68.8% male). All patients underwent a routine transthoracic echocardiography examination at baseline visit. Standard echocardiographic measurements were conducted according to recent guidelines. GLS was derived from the segmental averaging (18-segment) of the three apical views. M-mode MAPSE of septal and lateral walls were obtained from standard apical 4-chamber view. All patients completed at least one-year clinical follow-up by telephone interview or clinical visit. The primary endpoint was defined as all-cause mortality or heart transplantation (HTx). Results Over a median follow-up period of 27 (14–40) months, 259 (27.2%) patients died and 9 (0.9%) underwent HTx. MAPSE_septal was significantly lower in non-survivors than in survivors (6 (5–8) vs. 7 (5–8) mm, P=0.009), while LVEF (36% vs. 36%, P=0.927) and GLS (−9.6% vs. −9.8%, P=0.473) were similar between non-survivors and survivors. All-cause mortality was significant higher in patients with MAPSE_septal<5mm than those with MAPSE_septal ≥5mm (34.9% vs. 26.7%, P=0.032). All-cause death increased in proportion with increased severity of diastolic dysfunction (DD, 20.4%, 29.6% and 34.0% in patients with mild, moderate and severe DD, P=0.002). Multivariable Cox regression analysis showed that reduced MAPSE_septal (<5mm, HR=1.451, 95% CI=1.079–1.951, P=0.014) was independently associated with increased all-cause mortality adjusted for clinical confounders including age, sex, NYHA class, atrial fibrillation, diabetes, hyperuricemia, chronic respiratory diseases, sleep disturbance, while MAPSE_lateral, LVEF, and GLS were not outcome determinants in this patient cohort. Subgroup analysis showed that mild DD (n=269), reduced MAPSE_septal were significantly associated with increased all-cause mortality (adjusted HR=3.734, 95% CI=1.850–7.536, P<0.001), while MAPSE_septal was not a risk factor of all-cause mortality in the subgroup of moderate to severe DD (n=667, HR=1.314, P=0.108). Conclusions Septal MAPSE, but not LVEF or GLS, serves as an independent determinant of all-cause mortality in non-ischemic heart failure patients with reduced LVEF and mild diastolic dysfunction. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Federal Ministry of Education and Research