Background: Hypotensive events and drops in systolic blood pressure (SBP-drop) are frequent in patients hospitalized with acute heart failure. We investigated whether SBP-drops are associated with outcomes in patients treated with serelaxin. Methods: Patient-level retrospective analyses of 4 prospective trials investigating serelaxin in acute heart failure. Main inclusion criteria were SBP 125 to 180 mm Hg, pulmonary congestion, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide). SBP-drops were prospectively defined as SBP<100 mm Hg, or, if SBP remained >100 mm Hg, a drop from baseline of 40 mm Hg from baseline. Outcomes were a short-term composite outcome (worsening heart failure, hospital readmission for heart failure or all-cause mortality through 14 days) and 180-day mortality. Results: Overall, 2559/11 226 (23%) patients had an SBP-drop. SBP-drop, versus no SBP-drop, was associated with a worse outcome: cumulative incidence of 180-day mortality (11% versus 9%, hazard ratio [HR]. 1.21 [95% CI, 1.05–1.39]; P =0.009) and the short-term outcome (11% versus 9%, HR, 1.29 [95% CI, 1.13–1.49]; P <0.001). Of the 2 SBP-drop components, an SBP<100 mm Hg was associated with the worst outcome compared with a 40 mm Hg drop: short-term outcome (11% versus 10%) and HRs of 1.32 (95% CI, 1.13–1.55; P =0.0005) and 1.22 (95% CI, 0.97–1.56; P =0.09), for each component respectively, with a P value for interaction of 0.05. SBP-drops were associated with a worse short-term outcome in the placebo group (HR, 1.46 [95% CI, 1.19–1.79]; P =0.0003), but not in the serelaxin-group (HR, 1.18 [95% CI, 0.97–1.42]; P =0.10); P interaction=0.003. Conclusions: SBP-drops in patients with acute heart failure and normal to high SBP at admission is associated with worse short- and long-term outcomes especially for SBP <100 mm Hg. However, in patients treated with the intravenous vasodilator serelaxin, SBP-drops seemed less harmful. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02064868, NCT02007720, NCT01870778, NCT00520806.