OBJECTIVES: The aim of this study was to assess efficacy and safety of tenofovir (TDF) as compared to other nucleot(s)ide analogues (NAs), i.e. lamivudine (LAM), adefovir (ADV) and entecavir (ETV) in the treatment of chronic hepatitis B virus (HBV) infection. METHODS: Assessment was based on randomized controlled trials (RCTs) identified by means of systematic review, carried out according to the Cochrane Collaboration guidelines. Studies met the inclusion criteria if they directly compared at least two of following interventions: TDF, LAM, ADV, ETV or placebo. The electronic medical databases (EMBASE, MEDLINE, CENTRAL) were searched. Two reviewers independently selected trials, assessed their quality and extracted data. Mixed treatment comparison (MTC) was performed with WinBugs software. If feasible, subgroup analyses were performed according to hepatitis B antigen e (HBeAg) and or LAM resistance status.  RESULTS: We identified 30 relevant studies (6674 patients) with 12-144 weeks of follow-up . MTC showed that TDF increased the chance of HBV DNA clearance at the end of treatment period as compared to ADV (OR = 13,16 [3,21; 54,20]), LAM (OR = 61,09 [11,10; 503,78]) and ETV (OR = 9,55 [1,53; 76,98]). Subgroup analysis in HBeAg-positive subjects revealed that TDV was more effective than ADV (OR = 21,60 [1,67; 285,40]) and LAM with respect to HBV DNA clearance but no difference were found between TDV and ETV (OR = 11,24 [0,53; 342,57). TDF showed similar efficacy to other NAs with respect to normalization of alanine aminotransferase activity (ALT) and histological improvement. TDF did not increase the risk of any and serious adverse events either in comparison with PLC or with other NAs. The rates of ALT flares were similar in all groups. CONCLUSIONS: TDF demonstrated the highest efficacy with respect to reduction of viral load in patients with chronic HBV and maintained a very good safety profile.