<i>Background:</i> Previous studies have suggested that a lower lymphocyte ratio (Ly%) in the white blood cell (WBC) differential count is related to worse outcomes in patients with acute heart failure (AHF) and other cardiovascular disorders. <i>Methods:</i> In the Pre-RELAX-AHF study, 234 patients with AHF, systolic blood pressure >125 mm Hg and brain natriuretic peptide ≧350 pg/ml or equivalent were randomized to 1 of 4 intravenous doses of relaxin or placebo and followed up for 6 months following randomization. Complete blood count and differential were performed by a central laboratory at baseline and then daily to day 5 and on day 14. <i>Results:</i> The WBC count by itself was not associated with measures of disease severity or outcome, and patients with Ly% <13% had similar baseline characteristics to patients with Ly% >13%, except for a higher baseline WBC count, elevated baseline glucose, older age and higher rates of peripheral vascular disease. However, patients with Ly% <13% had less improvement of dyspnea, greater worsening of heart failure, longer length of initial hospital stay and fewer days alive and out of hospital. Statistical significance was reached for all-cause death by days 60 and 180 (hazard ratio = 1.11 per percent decrease, 95% confidence interval 1.03–1.19; p = 0.0048). <i>Conclusions:</i> Despite no association with any baseline characteristic known to strongly predict outcome in AHF, low Ly% is associated with less symptom relief and worse in-hospital and postdischarge clinical outcomes.