Platelet transfusions are commonly used in non-bleeding preterm babies with thrombocytopenia. In our multicentre randomised trial (PlaNet-2/MATISSE) preterm babies who developed severe thrombocytopenia were assigned to platelet transfusions at thresholds of 25×10⁹/L or 50×10⁹/L. Bleeding was documented using a validated bleeding assessment tool. The primary outcome was mortality or major bleeding within 28 days. Secondary outcomes included bronchopulmonary dysplasia (BPD), retinopathy of prematurity, rates of sepsis or necrotizing enterocolitis. Six hundred and sixty babies (median birthweight 740g and 26 weeks gestational age) were randomised. 90% (296/328) of<50×10⁹/L group versus 53% (177/331) of <25×10⁹/L group received at least one transfusion. 26% (85/324) of<50×10⁹/L group and 19% (61/329) of<25×10⁹/L group had a new major bleed or died by study day 28 (OR 1.57,95% CI:1.06–2.32;P=0.02). Sixty-three percent (169/269) of<50×10⁹/L group developed BPD versus 54% (153/281) of <25×10⁹/L group (OR 1.54, 95% CI: 1.03–2.30). The trial conclusions were that among preterm babies with severe thrombocytopenia, those randomised to receive platelet transfusions at a platelet count threshold<50×10⁹/L had a higher rate of mortality/major bleeding within 28 days of randomisation than those in the <25×10⁹/L group. Platelets have multiple immunological and inflammatory effects which may mediate the harm seen in this study. Neonates receive disproportionately larger volume transfusion volumes compared to adults and haemodynamic effects may play a role in increased bleeding. Harmful effects of platelets may also be mediated by ABO incompatibility or increased storage age.