Background <p>Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE), affecting up to one-third of pediatric SLE patients. Timely induction therapy is critical in proliferative LN to prevent progression to kidney failure or death. Intravenous cyclophosphamide (IVCP) has long been a standard induction agent, but its toxicity profile has prompted interest in mycophenolate mofetil (MMF) as a potentially safer alternative. However, data comparing the efficacy and safety of MMF versus IVCP in children are limited and inconclusive.</p> Objectives <p>To systematically review and synthesise existing evidence comparing the efficacy and safety of MMF versus IVCP for induction therapy in pediatric patients with proliferative LN.</p> Data sources <p>A comprehensive search was conducted in six electronic databases (PubMed, EMBASE, Web of Science, SCOPUS, CINAHL, and CENTRAL) on June 2, 2025. Reference lists of included articles were also manually screened.</p> Study eligibility criteria <p>We included randomised controlled trials and observational studies published in English that directly compared MMF and IVCP as induction therapies in pediatric patients with biopsy-proven proliferative LN. Studies were required to report at least one of the following outcomes: kidney remission (complete or partial), adverse events, kidney failure, or death.</p> Participants and interventions <p>Eligible participants were children aged ≤ 17&#xa0;years with a diagnosis of proliferative LN based on the American College of Rheumatology (ACR) criteria. Interventions involved MMF plus corticosteroids versus IVCP plus corticosteroids, with comparable adjunctive therapies.</p> Study appraisal and synthesis methods <p>Authors independently screened articles, extracted data, and assessed study quality using the RoB2 tool for RCTs and the ROBINS-I tool for observational studies. A random-effects meta-analysis was conducted to estimate pooled risk ratios (RRs) for complete remission. Sensitivity analyses and funnel plots were used to assess robustness and publication bias.</p> Results <p>Out of 1,633 screened records, seven studies met the inclusion criteria, six observational studies (<i>n</i> = 282) and one RCT (<i>n</i> = 24). Meta-analysis of the observational studies revealed no significant difference in complete remission between the MMF and IVCP groups (pooled RR: 1.01; 95% CI: 0.78–1.29; I² = 0%). The RCT reported similar findings, with remission rates of 70% (MMF) vs. 57.1% (IVCP) (<i>p</i> = 0.527). Adverse event rates were comparable, but IVCP showed more frequent non-infectious complications (e.g., leukopenia, hemorrhagic cystitis, alopecia). No deaths were reported.</p> Limitations <p>The analysis was limited by the predominance of observational studies and only one small pediatric RCT with a high risk of bias. Variability in outcome definitions, inconsistent reporting of baseline disease severity, and lack of subgroup analysis limited further interpretation. Small study numbers precluded a formal assessment of publication bias.</p> Conclusions and implications of key findings <p>The efficacy of MMF appears to be similar to IVCP for induction therapy in pediatric proliferative LN, with a potentially more favourable safety profile. These findings support MMF as a viable alternative to IVCP; however, robust, multicenter pediatric RCTs are urgently needed to establish definitive treatment recommendations and guide clinical practice.</p> Systematic review registration number <p>PROSPERO: CRD42024533313 available from: <a href="https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024533313">https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024533313</a></p> Graphical Abstract <p></p>