BACKGROUND: In acute heart failure (AHF), systolic blood pressure (SBP) is an important clinical variable. This study assessed the association between SBP and short-term and long-term outcomes in a large cohort of patients with AHF. METHODS AND RESULTS: This is an analysis of 4 randomized controlled trials investigating serelaxin versus placebo in patients admitted with AHF and SBPs from 125 to 180 mm Hg. Outcomes were 180-day all-cause mortality and a composite end point of all-cause mortality, worsening heart failure, or hospital readmission for heart failure the first 14 days. Left ventricular ejection fraction (LVEF) was examined as LVEF<40% and LVEF≥40%. Multivariable Cox regression models were adjusted for known confounders of outcomes in AHF. A total of 10 533 patients with a mean age of 73 (±12) years and a mean SBP of 145 (±7) mm Hg were included. LVEF was assessed in 9863 patients (93%); 4737 patients (45%) had LVEF<40%. Increasing SBP was inversely associated with 180-day mortality (adjusted hazard ratio [HRadjusted], 0.93; 95% CI, 0.89–0.98; P=0.008 per 10 mm Hg increase) and with the composite end point (HRadjusted, 0.90; 95% CI, 0.85–0.94; P<0.001 per 10 mm Hg increase). A significant interaction with LVEF was observed, revealing that SBP was not associated with mortality in patients with LVEF≥40% (HRadjusted, 0.98; 95% CI, 0.91–1.04; per 10 mm Hg increase), but was strongly associated with increased mortality in LVEF<40% (HRadjusted, 0.84; 95% CI, 0.77–0.92; per 10 mm Hg increase). CONCLUSIONS: Elevated SBP is associated with favorable short-term and long-term outcomes in patients with AHF. In our predefined subgroup analysis, we found that baseline SBP was not associated with mortality in LVEF≥40%, but was strongly associated with mortality in patients with LVEF<40%.