Importance Berberine is a potential therapy for metabolic disorders, yet its effects on visceral adipose tissue (VAT) and liver fat remain uncertain. Objectives To evaluate the efficacy and safety of berberine in reducing VAT area and liver fat content in diabetes-free individuals with obesity and metabolic dysfunction–associated steatotic liver disease (MASLD). Design, Setting, and Participants In this multicenter, double-blind randomized clinical trial, diabetes-free individuals with obesity and MASLD were enrolled at 11 hospitals in China between July 6 and December 29, 2023, with a follow-up duration of 6 months. Interventions Participants were randomly assigned to receive either oral berberine, 1 g/d, or a matching placebo. Main Outcomes and Measures The primary outcomes were relative percentage change in VAT area and absolute change in liver fat content assessed by computed tomography. Other outcomes included changes in parameters of glucose, lipids, and inflammation. Analyses were conducted according to the intention-to-treat principle. Results Among 337 randomized participants (mean SD age, 41.8 10.6 years; 221 65.6% male), 169 received berberine and 168 placebo. The mean (SD) medication adherence rates were 90.3% (14.7%) for berberine and 90.7% (17.4%) for placebo. No significant differences were observed between study arms for VAT area (1.4% 97.5% CI, −2.4% to 5.2%) or liver fat content (0.9% 97.5% CI, −0.4% to 2.1%). Berberine was associated with larger reductions in low-density lipoprotein cholesterol (−7.72 [95% CI, −13.13 to −1.93 mg/dL), apolipoprotein B (−3.42 95% CI, −6.33 to −0.51 mg/dL) and high-sensitivity C-reactive protein (hs-CRP) (−0.072 95% CI, −0.140 to −0.004 mg/dL) vs placebo, but not other secondary outcomes. The incidence of adverse events was similar between study arms. Post hoc analyses suggested consistent patterns of larger reductions in low-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP levels in participants with higher baseline hs-CRP levels. Conclusions and Relevance In this randomized clinical trial of diabetes-free individuals with obesity and MASLD, a 6-month berberine treatment at a daily dose of 1 g had an excellent safety profile but did not reduce VAT area or liver fat content. Trial Registration ClinicalTrials.gov Identifier: NCT05647915
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