ObjectiveTo systematically review the efficacy and safety of interferon-alpha (IFN-α) combined with enticavir (ETV) for treatment-naïve chronic hepatitis B (CHB) patients, so as to provide references for clinical practice. MethodsWe electronically searched databases including PubMed, EMbase, The Cochrane Library (Issue 7, 2015), Web of Science, WanFang Data, CNKI, CBM and VIP from inception to July 20th, 2015, to collect randomized controlled trials (RCTs) about IFN-α combined with ETV versus IFN-α or ETV monotherapy for treatment-naïve CHB patients. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software. ResultsA total of 10 RCTs involving 964 patients were included. The results of meta-analysis showed that:For HBV-DNA loss rate, HBeAg loss rate and HBeAg seroconversion rate, there were no significant differences between the combination therapy group and the monotherapy group at 12-week of treatment, but the combination therapy group was significantly superior to the monotherapy group at 24-and 48-week of treatment except that there was no significant difference between the combination therapy group and the IFN-α monotherapy group in HBeAg seroconversion at 48-week of treatment. For rate of ALT normalization, the combination therapy group was superior to the IFN-α monotherapy group at 12-and 24-week of treatment, but there were no significant differences between the combination therapy group and the ETV monotherapy group at 12-, 24-, and 48-week of treatment. For safety, no pooled analysis was performed because different outcomes were reported by included studies. ConclusionIFN-α combined with ETV is superior to IFN-α or ETV monotherapy in decreasing viral load, and promoting HBeAg loss and HBeAg seroconversion for treatment-naïve CHB patients, but the evidence of safety is insufficient. Due to the limited quantity and quality of included studies, the aforementioned conclusions still need to be further verified by conducting more large-scale, high quality RCTs.