Some patients have heard that nucleoside analogs have direct antiviral effects and fast efficacy; interferon is mainly immunomodulatory and long-lasting, so they can’t help but think that if combined treatment, won’t they complement each other’s strengths and weaknesses? In fact, medical doctors have made similar judgments and have received positive answers after continuous exploration. The mechanisms of the two classes of anti-hepatitis B viral drugs can complement each other: the key to the treatment of chronic hepatitis B is antiviral therapy, and antiviral drugs are currently available in two completely different mechanisms: interferons and nucleoside analogues. Nucleoside analogs inhibit the virus directly and can reduce serum virology levels more rapidly, thereby moderating the disease; however, these drugs have no immune boosting effect and are prone to relapse after discontinuation of the drug. Interferons are immunomodulators that can stimulate the body’s immunity against the virus and even clear cccDNA in the liver, although there are individual differences in stimulating immunity and not every patient can have efficacy, but in patients with effective treatment, the efficacy is durable and stable, and the long-term results in preventing cirrhosis and hepatocellular carcinoma are certain. The efficacy of combination therapy holds promise: A growing number of studies have found that combination therapy does improve outcomes. Based on this evidence, the 2015 APHIS guidelines affirm the efficacy of combination therapy, clearly stating that combination therapy “holds promise. Two combination therapy regimens are currently of interest: one is used concurrently and the other is used in nucleoside treated patients. An international, multicenter study demonstrated that the combination of long-acting interferon with nucleoside therapy reduced surface antigen levels more than nucleoside and long-acting interferon alone, resulting in more patients achieving surface antigen clearance, which means that patients treated with combination therapy have a better chance of achieving surface antigen clearance and clinical cure. Combination therapy in nucleoside treated patients has also shown encouraging results, with several studies, including the OSST study NEW SWITCH study, suggesting that the addition of long-acting interferon therapy to patients being treated with nucleosides improves e antigen conversion and surface antigen clearance, meaning that patients being treated with nucleosides are expected to have a shorter course of treatment and be free from lifelong treatment. In conclusion, combination therapy allows two different classes of antivirals with different mechanisms to work synergistically and provide better efficacy. However, which patients are more suitable to receive combination therapy and how to stop the drugs after the combination therapy need to be judged specifically according to each patient’s specific situation, and more research needs to be explored.