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Eightteen randomized controlled trials (hydroxyurea [<jats:italic>n<\/jats:italic>\u00a0=\u00a07], <jats:sc>l<\/jats:sc>\u2010arginine [<jats:italic>n<\/jats:italic>\u00a0=\u00a03], antiplatelets [<jats:italic>n<\/jats:italic>\u00a0=\u00a02], immunotherapy\/monoclonal antibodies [<jats:italic>n<\/jats:italic>\u00a0=\u00a02], sulfates [<jats:italic>n<\/jats:italic>\u00a0=\u00a02], docosahexaenoic acid [<jats:italic>n<\/jats:italic>\u00a0=\u00a01], niprisan [<jats:italic>n<\/jats:italic>\u00a0=\u00a01]) were analyzed. SUCRA and SMAA demonstrated that hydroxyurea at higher doses (30\u00a0mg\/kg\/day) or at fixed doses (20\u00a0mg\/kg\/day) and immunotherapy\/monoclonal antibodies are more effective for preventing vaso\u2010occlusive crisis (i.e., lower probabilities of incidence of this event; 14, 25, and 30%, respectively), acute chest syndrome (probabilities ranging from 8 to 30%), and needing of transfusions (11\u201331%), while <jats:sc>l<\/jats:sc>\u2010arginine (100\u2013200\u00a0mg\/kg) and placebo were more prone to these events. Therapies were overall considered safe; however, antiplatelets and sulfates may lead to more severe adverse events. 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