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Background: The short shelf‐life of liquid‐stored platelets (LP) at 20–24°C poses shortage and wastage challenges. Cryopreserved platelets have significantly extended shelf‐life, and were safe and efficacious for therapeutic transfusions of bleeding patients in the Afghanistan conflict and phase 2 randomized studies. Although hematology patients account for half of platelets demand, there is no randomized study on prophylactic cryopreserved platelet transfusions in them. Methods: We performed a phase 1b/2a randomized cross‐over study comparing the safety and efficacy of cryopreserved buffy coat‐derived pooled platelets (CP) to LP in the prophylactic transfusions of thrombocytopenic hematology patients. Results: A total of 18 adults were randomly assigned 1:1 to CP and LP for their first thrombocytopenic period (TP) of up to 28‐days. A total of 14 crossed over to the other platelet‐arm for the second TP. Overall, 17 subjects received 51 CP and 15 received 52 LP. CP‐arm had more treatment emergent adverse event (29.4% vs. 13.3% of subjects, 9.8% vs. 3.8% of transfusions) than LP‐arm but all were mild. No thromboembolism was observed. Both arms had similar bleeding rates (23.5% vs. 26.7% of subjects) which were all mild. Subjects in CP‐arm had lower average corrected count increments than LP‐arm (mean [SD] 5.6 [4.20] vs. 22.6 [9.68] ×109/L at 1–4 h, p <.001; 5.3 [4.84] vs. 18.2 [9.52] ×109/L at 18–30 h, p <.001). All TEG parameters at 1–4 h and maximum amplitude (MA) at 18–30 h improved from baseline post‐CP transfusion (p <.05) though improvements in K‐time and MA were lower than LP (p <.05). Discussion: During shortages, CP may supplement LP in prophylactic transfusions of thrombocytopenic patients. [ABSTRACT FROM AUTHOR]