Tenofovir disoproxil fumarate (TDF) and entecavir are recommended as first-line treatments for chronic hepatitis B virus (HBV) infection. However, there is debate over the comparative effectiveness of these drugs in preventing hepatocellular carcinoma (HCC). We performed a systematic review and meta-analysis of the effectiveness of TDF vs entecavir in reducing the incidence of HCC among patients with chronic HBV infection.We performed a systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library from 2010 through 2019 for full-text articles and conference abstracts on studies of effects of TDF vs entecavir in patients with HBV infection. Extracted data were analyzed with the random effects model. Potential sources of heterogeneity were investigated using sensitivity, meta-regression, and subgroup analyses.Our final analysis comprised 15 studies (61,787 patients; 16,101 patients given TDF and 45,686 given entecavir). TDF treatment was associated with a significantly lower risk of HCC than entecavir (hazard ratio, 0.80; 95% CI, 0.69-0.93; P=.003; I2=13%). The lower risk of HCC in patients given TDF compared with entecavir persisted in sensitivity and subcohort analyses performed with propensity score-matched cohorts and cirrhosis subcohorts. Inclusion of patients with decompensated cirrhosis and the sample size were the factors with the largest effects on between-study heterogeneity in meta-regression analyses. Subsequent subgroup analyses revealed no statistical differences in the incidence of death or transplantation (hazard ratio, 0.93; 95% CI, 0.73-1.17; P=.519; I2=6%) between patients given TDV vs entecavir.In a meta-analysis of studies of patients with chronic HBV infection, we found that TDF treatment was associated with a significantly lower (20%) risk of HCC than entecavir treatment. Randomized trials are needed to support this finding.