OBJECTIVES: Autoimmune Hepatitis (AIH) is a chronic inflammatory liver disease with significant morbidity and mortality if untreated. Current first-line treatment involves corticosteroids and azathioprine (AZA), which are effective but are associated with significant adverse effects and treatment intolerance. Mycophenolate mofetil (MMF), an immunosuppressive agent with a potentially better safety profile, has emerged as an alternative. This meta-analysis evaluated the efficacy and safety of MMF compared to AZA in treatment-naïve AIH patients. METHODS: We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Databases were searched for articles published up to May 2024. Statistical analysis was performed using RevMan, employing a random-effects model. RESULTS: Five studies involving 621 patients were included. MMF showed significantly higher rates of complete biochemical response compared to AZA (odds ratio [OR] 3.64, 95% confidence interval [CI] 2.07-6.40, p <
0.00002) and lower non-response rates (OR 0.45, 95% CI 0.24-0.85, p = 0.01). Corticosteroid withdrawal rates were also higher in the MMF group (OR 2.89, 95% CI 1.69-4.94, p = 0.0002). Relapse rate and cumulative prednisolone dose were comparable between the two groups. MMF demonstrated a better safety profile, with significantly lower rates of gastrointestinal symptoms (OR 0.46, 95% CI 0.27-0.79, p = 0.005). CONCLUSIONS: MMF shows superior efficacy and tolerability compared to AZA in treatment-naïve AIH patients and may serve as a preferred first-line therapy, offering improved patient adherence and clinical outcomes. Further randomized controlled trials are warranted to confirm these findings.