Background  Chronic hepatitis B (CHB) infection leads to development of hepatocellular carcinoma (HCC), but the effects of treatment in preventing HCC are not clear.

Aim  To study the effects of interferon (IFN) or nucleoside/tide analogue (NA) on the risk of developing HCC in CHB patients.

Methods  Randomized trials, case–control and cohort studies were retrieved from five electronic databases and international conferences over the past 10 years. Relative risks (RRs) of HCC with or without treatment were studied.

Results  Twelve studies (n = 2742) enrolling patients treated by IFN vs. control showed that the risk of HCC after treatment was reduced by 34% (RR: 0.66, 95% CI: 0.48–0.89). Benefit is more significant among patients with early cirrhosis than among those without cirrhosis. Five studies (n = 2289) compared patients treated by NA with control. The risk of HCC after treatment was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50). HBeAg-positive patients showed more significantly reduced HCC risk with treatment. Patients without cirrhosis benefited more from NA than those with cirrhosis. Resistance to NA has obviated the benefit of the treatment.

Conclusions  IFN or NA treatment significantly reduces risk of HCC. While IFN benefited patients with cirrhosis, NA benefited patients with no cirrhosis and HBeAg-positive CHB infection.