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Objectives: To evaluate whether there is evidence of efficacy of the most commonly used medications in their primary indications., Study Design and Setting: This scoping review was executed using the Cochrane Library and MEDLINE databases up to May 2023. The 10 most prescribed medications in England, France, and the United States were identified using country-specific public databases. Up to 3 common indications in primary care were defined for each medication, based on a survey of general practitioners. The outcomes were determined by the authors to be patient-important outcomes, with placebo as the comparator. Two investigators independently conducted searches, following a predefined algorithm, to identify randomized controlled trials or meta-analyses of randomized controlled trials assessing the efficacy of these medications for each indication. The risk of bias was assessed using the ROBIS or ROB 2.0 tools., Results: We identified 21 drugs, covering 56 indications and 114 outcomes. Sixty-seven percent of the evaluated medications demonstrated efficacy for at least one outcome in at least one of the sought indications. Overall, evidence of efficacy was found for 48% of the indications. There was no study evaluating the efficacy of amoxicillin and salbutamol. For other drugs such as phloroglucinol or cholecalciferol, available studies suggested an absence of efficacy in the most common indications., Conclusion: This study underscores the lack of data regarding the level of evidence for the most prescribed medications. Limitations include the choice of outcomes, and the understanding that the absence of evidence is not synonymous with the absence of efficacy., Competing Interests: Declaration of competing interest All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/and declare: no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)