Purpose Liquid-stored platelets have a 7-day shelf-life. Cryopreservation extends this to two years, avoiding shortages, preventing wastage, and allowing smaller hospitals to transfuse platelets. However, evidence is limited to preclinical studies and small clinical trials. Cryopreservation might enhance haemostatic activity, but this remains uncertain. Methodology CLIP-II was a double-blind randomised non-inferiority trial conducted between August 2021 and April 2024 in 11 Australian hospitals. High-risk cardiac surgery patients deemed by their clinicians to require platelet transfusion were randomised to up to three units of cryopreserved group O platelets resuspended in plasma or liquid-stored platelets. Additional platelets, if necessary, were liquid-stored platelets. The primary outcome was chest drain blood loss in the first 24 hours after ICU admission. Pilot data showed 202 transfused patients would provide >90% surety that the limit of a 95% confidence interval was not above the set 20% non-inferiority margin if this were the case. Results In total, 388 patients were randomised, of whom 105 received liquid-stored and 98 received cryopreserved platelets. One transfused patient was palliated before outcome data was collected. Patients were well-matched at baseline: mean age 64.3 years; 30% urgent or emergency surgery; median [IQR] Euroscore risk 3.39 [2.16-7.05]. Patients most commonly underwent aortic valve replacement (51%), aortic root surgery (38%), or coronary artery bypass grafts (35%); often a combination of these or other procedures. A median of 2 [1-2] study platelet units were transfused, most commonly (87%) initiated in the operating theatre. Hospital mortality was 6.9%. Full outcome data is currently being validated against source information, and will be available in mid-2024. Conclusion If cryopreserved platelets are non-inferior or superior to liquid-stored platelets, CLIP-II will support registration and widespread use in bleeding patients.