Background: Treatment with sacubitril-valsartan reduces mortality and heart failure (HF) events in HF with reduced ejection fraction and may reduce HF hospitalization in women with HF with preserved ejection fraction. Methods: EVALUATE-HF randomized 464 participants (109 women) with HF with reduced ejection fraction to sacubitril-valsartan or enalapril for 12 weeks. Documented left ventricular ejection fraction (LVEF) ≤0.40 within the prior 12 months was required, although core laboratory LVEF>0.40 was permitted. Assessments of aortic stiffness (pulse pressure and characteristic impedance, Z _c ) were performed at baseline and at trough and 4 hours postdose at weeks 4 and 12. Results: In models of change from baseline adjusted for baseline value, treatment with sacubitril-valsartan produced greater overall reductions in mean arterial pressure (treatment group difference, −3.0±0.8 mm Hg, P <0.001) and pulse pressure (−3.0±0.8 mm Hg, P <0.001). Postdose reductions in Z _c were greater in the sacubitril-valsartan group (−16±6 dyne×second/cm ⁵ , P =0.012). Post hoc analyses found evidence of effect modification by LVEF (interaction P =0.036). With LVEF<0.40, postdose reductions in Z _c were greater in the sacubitril-valsartan group (trough, −3±8 dyne×second/cm ⁵ versus post-dose, −17±8 dyne×second/cm ⁵ ; interaction P =0.024) with no sex difference (treatment×sex interaction, P =0.3). With LVEF≥0.40, treatment with sacubitril-valsartan was associated with greater overall reductions in Z _c in women (women, −80±21 dyne×second/cm ⁵ versus men, −20±13 dyne×second/cm ⁵ ; interaction P =0.019). Conclusions: In prespecified analyses that include pre- and postdose assessments at 4 and 12 weeks, treatment with sacubitril-valsartan was associated with greater postdose reductions in aortic Z _c . In a post hoc analysis, sacubitril-valsartan was associated with sustained reductions in Z _c in women with LVEF≥0.40. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02874794.