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To evaluate the efficacy and safety of genus Phyllanthus for chronic hepatitis B virus (HBV) infection we performed a systematic review of randomized clinical trials. Randomized trials comparing genus Phyllanthus vs. placebo, no intervention, general nonspecific treatment, other herbal medicine, or interferon treatment for chronic HBV infection were identified by electronic and manual searches. Trials of Phyllanthus herb plus interferon (IFN) vs. IFN alone were also included. No blinding and language limitations were applied. The methodological quality of trials was assessed by the Jadad scale plus allocation concealment. Twenty-two randomized trials (n =1947) were identified. The methodological quality was high in five double-blind trials and low in the 17 remaining trials. The combined results showed that Phyllanthus species had positive effect on clearance of serum HBsAg (relative risk 5.64, 95% CI 1.85–17.21) compared with placebo or no intervention. There was no significant difference on clearance of serum HBsAg, HBeAg and HBV DNA between Phyllanthus and IFN. Phyllanthus species were better than nonspecific treatment or other herbal medicines for the clearance of serum HBsAg, HBeAg, HBV DNA, and liver enzyme normalization. Analyses showed a better effect of the Phyllanthus plus IFN combination on clearance of serum HBeAg (1.56, 1.06–2.32) and HBV DNA (1.52, 1.05–2.21) than IFN alone. No serious adverse event was reported. Based on this review Phyllanthus species may have positive effect on antiviral activity and liver biochemistry in chronic HBV infection. However, the evidence is not strong due to the general low methodological quality and the variations of the herb. Further large trials are needed.