OBJECTIVES: To evaluate the feasibility of randomizing children on extracorporeal membrane oxygenation (ECMO) to one of two prophylactic platelet transfusion thresholds. DESIGN: Randomized controlled trial. SETTING: Ten ECMO centers (nine in United States, one in Israel). PATIENTS: Critically ill children (0 to younger than 18 yr), supported on ECMO, with no or minimal bleeding within 24 hours of cannulation. INTERVENTIONS: Children were randomized to a higher platelet threshold (transfused when platelet count < 90 √ó 109/L) or a lower platelet threshold (transfused when platelet count < 50 √ó 109/L). Primary feasibility outcome was pre-transfusion platelet count to test for a difference between strategies. Primary safety outcome was progression to severe bleeding, severe clotting, and/or all-cause mortality. MEASUREMENTS AND MAIN RESULTS: Of 159 patients screened for eligibility, 77% (123/159) met eligibility criteria. Sixty-five percent (80/123) of caregivers were approached for consent. Consent was obtained in 63% (50/80). Enrolled children had a median age of 0.2 years (interquartile range 0.0; 1.7) and 88% (44/50) were supported by veno-arterial (V-A) ECMO. The model-adjusted mean difference in pre-transfusion platelet count between the groups was 32 √ó 109/L (p < 0.001). Compliance with assigned transfusion threshold was 99.2%. Eleven (22%) children experienced the primary safety outcome. Progression to severe bleeding occurred in 14% (7/50) of patients, whereas progression to severe clotting was observed in 4% (2/50). CONCLUSIONS: Non-bleeding children on ECMO can be screened, enrolled and randomized to different platelet transfusion strategies within 24 hours of cannulation. Compliance with the protocol was excellent with significant separation in pre-transfusion platelet counts between the arms. Severe bleeding and severe clotting occurred at similar rates in both thresholds. A larger, definitive trial is feasible and needed.