Background: Prophylactic platelet transfusions are frequently used to prevent bleeding in hospitalised patients with thrombocytopenia. Recommendations regarding the use of prophylactic platelet transfusions in non-haematological patients are based on extrapolations, observational studies, and expert opinions, and transfusion with platelets has been associated with adverse effects. We aim to assess the overall benefits and harms of prophylactic platelet transfusions in hospitalised patients with thrombocytopenia. Methods/Design: We will conduct a systematic review with meta-analyses and trial sequential analyses in compliance with the recommendations by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We will prepare the manuscript in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. We will include randomised clinical trials assessing prophylactic platelet transfusion versus no prophylaxis or placebo in hospitalised patients with thrombocytopenia. The primary outcome is mortality at longest follow-up. Secondary outcomes include episodes of clinically important bleeding, nosocomial infections, transfusion-related adverse events, thromboembolic events, length of hospital stay, quality of life, and days alive without the use of life support. We will conduct prespecified subgroup analyses and sensitivity analyses and assess the risk of random errors by trial sequential analyses. Discussion: The proposed systematic review will provide an overview of the certainty of evidence for the benefits and harms of prophylactic platelet transfusion in hospitalised patients with thrombocytopenia.