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Introduction: Approximately 5%-10% of individuals with untreated latent tuberculosis infection (LTBI) will progress to active tuberculosis (TB). Children are at a higher risk for progression to TB disease than adults. Isoniazid prophylaxis treatment period is long and can cause liver damage. Alternatives to isoniazid, such as rifamycin containing regimens, should be considered for prophylaxis. Previous systematic reviews, with different study designs and data combining results on children and adults, have evaluated the comparative efficacy and harms of LTBI treatment regimens. We aim to determine the effectiveness and safety of all the different regimens available for the treatment of LTBI for children and adolescents less than 18 years of age, contacts of drug-susceptible TB, without HIV infection., Methods and Analysis: MEDLINE, Embase and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials without any language or publication date restriction. Screening and extraction will be performed in duplicate. Risk of bias will be performed in duplicate with Cochrane Risk of Bias tool V.2. Pairwise meta-analysis of direct comparisons and network meta-analyses (NMAs) will be performed. Heterogeneity will be assessed using I 2 and Cochrane thresholds. Direct and indirect estimates in an NMA will be combined if justifiable. Subgroups analyses will be performed in different mean age and study year groups. Sensitivity analysis based on the risk of bias will be conducted. Publication bias will be investigated using funnel plots and Egger's regression test. Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria will assess certainty of the evidence for the direct comparisons. GRADE approach for NMA will assess the quality of the evidence from the indirect and NMA., Ethics and Dissemination: Ethical approval is not required as no primary data are collected. This systematic review will be disseminated in a peer-reviewed journal., Prospero Registration Number: CRD42021271512., Competing Interests: Competing interests: VS-J attended a Master Class on Reproductive and Evidenced-Based Medicine financed by Abbott Laboratories, a Medical Health Update Conference financed by Sanofi Aventis, and was a speaker for Virtual Training in Primary Healthcare financed by Lafrancol S.A.S. The other authors certify that they have no affiliations with or involvement in any organisation or entity with any financial or non-financial interest in the subject matter or materials discussed., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)