Background. Platelet dysfunction is a major cause of excessive microvascular bleeding after cardiac surgery. A new point-of-care test (hemoSTATUS) can identify patients at risk of excessive bleeding. We aimed to find out whether patients who can benefit from desmopressin during cardiac surgery can be identified by this test. Methods. We enrolled 203 patients scheduled for elective cardiac surgery in a prospective, double-blind, placebo-controlled trial. Patients with abnormal hemoSTATUS clot-ratio results (< 60% of maximum in channel 5) after discontinuation of cardiopulmonary bypass were randomly assigned desmopressin (n = 50) or placebo (n = 51). Patients with normal clot ratios were included in an untreated control group (n = 72). Findings. Intraoperative platelet counts and clot ratios were significantly higher in the untreated control group than in the study-drug groups. In intensive care, clot ratios in patients who received desmopressin were similar to those in the untreated control group, despite significantly lower platelet counts, but were lower in the placebo group than in the other two groups (p = 0.0001). Compared with the placebo group, patients who received desmopressin had less blood loss in 24 h (mean 624 [SD 209] vs 1028 mL  p = 0.0004) and required less transfusion of red blood cells (1.1  vs 2.2 U [0.32] p = 0.009), platelets (0.1 [0.04] vs 1.9 U [4.5] p = 0.0001), and fresh-frozen plasma (0.1 [0.07] vs 0.75 U [0.21] p = 0.0008), and had less total blood-donor exposures (1.56 [0.31] vs 5.2 [0.8] p = 0.0001). Placebo patients also had substantially higher blood loss and transfusion requirements than untreated control patients. Interpretation. Patients identified with hemoSTATUS as being at increased risk of excessive bleeding after cardiac surgery can benefit from administration of desmopressin. Further studies are, however, needed to confirm these findings as well as to identify the mechanism of action and safety of desmopressin in the clinical setting.