Introduction: Neonatal thrombocytopenia is a common and important clinical problem in preterm neonates. A trial assessing clinically relevant outcomes in relation to the different platelet count thresholds used to trigger transfusion has never been undertaken in preterm neonates with severe thrombocytopenia. Objectives: Platelets for Neonatal Transfusion - Study 2 (PlaNeT-2) aims to assess whether a higher prophylactic platelet transfusion threshold is superior to the lower thresholds in current standard practice in reducing the proportion of patients who have a major bleed or die up to study day 28. Methods: PlaNeT-2 is a two-stage, randomised, parallel-group, superiority trial. PlaNet-2 compares clinical outcomes in preterm neonates (<34 weeks' gestation at birth) randomised to receive prophylactic platelet transfusions to maintain platelet counts at or above either 25 × 109/l or 50 × 10 9/l. The primary outcome measure is the proportion of patients who either die or experience a major bleed up to and including study day 28. A total of 660 infants will be randomised. Results and Conclusions: This trial will help define optimal platelet transfusion support for severely thrombocytopenic preterm neonates by evaluating the risks and benefits of two different prophylactic neonatal platelet transfusion thresholds.