Chronic hepatitis B (CHB) is a major global health problem caused by hepatitis B virus (HBV) infection, and can put patients at high risk of death from cirrhosis and liver cancer. However, CHB can be treated with nucleos(t)ide analogues. We aimed to evaluate the effectiveness and safety of nucleos(t)ide analogues for the treatment of CHB patients.: A systematic literature search was performed. Direct comparison meta-analyses and network meta-analysis (NMA) were carried out.: Thirty-six randomized controlled trials (RCTs) met inclusion criteria. Compared with placebo, the nucleos(t)ide analogs were all effective in HBeAg seroconversion, HBeAg loss and achieving undetectable HBV DNA. Telbivudine was associated with higher HBeAg seroconversion compared with entecavir. For HBeAg loss rate and proportion of achieving undetectable HBV DNA, tenofovir ranked as the best. Entecavir might be the most potent in the normalization of alanine aminotransferase (ALT). The nucleos(t)ide analogs did not have higher serious adverse events rate as compared with placebo.: The nucleos(t)ide analogs are all effective for HBeAg seroconversion, HBeAg loss, undetectable HBV DNA and most are effective for ALT normalization in adults with CHB. RCTs of multi-center, low risk of bias and long-term follow-up are still needed.