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 [HR _adjusted ], 0.93; 95% CI, 0.89–0.98; P =0.008 per 10 mm Hg increase) and with the composite end point (HR _adjusted , 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% (HR _adjusted , 0.98; 95% CI, 0.91–1.04; per 10 mm Hg increase), but was strongly associated with increased mortality in LVEF<40% (HR _adjusted , 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%.