This randomized controlled trial aimed to assess the effect of biannual screening with a combination of alpha-fetoprotein (AFP) and ultrasonography on hepatocellular carcinoma (HCC) mortality in people at increased risk in urban Shanghai, China. The study included 18,816 participants aged 35–59 years with hepatitis B virus infection or a history of chronic hepatitis. Participants were randomly allocated to a screening group (9,373) or a control group (9,443). The screening group received an AFP test and ultrasonography examination every 6 months, while the control group did not receive any screening. The study followed up all participants until December 1998. The primary outcome measure was HCC mortality. The results showed that the screened group had a significantly lower HCC mortality rate (83.2/100,000) compared to the control group (131.5/100,000), with a mortality rate ratio of 0.63 (95% CI 0.41–0.98). The study concluded that biannual screening reduced HCC mortality by 37%.This randomized controlled trial aimed to assess the effect of biannual screening with a combination of alpha-fetoprotein (AFP) and ultrasonography on hepatocellular carcinoma (HCC) mortality in people at increased risk in urban Shanghai, China. The study included 18,816 participants aged 35–59 years with hepatitis B virus infection or a history of chronic hepatitis. Participants were randomly allocated to a screening group (9,373) or a control group (9,443). The screening group received an AFP test and ultrasonography examination every 6 months, while the control group did not receive any screening. The study followed up all participants until December 1998. The primary outcome measure was HCC mortality. The results showed that the screened group had a significantly lower HCC mortality rate (83.2/100,000) compared to the control group (131.5/100,000), with a mortality rate ratio of 0.63 (95% CI 0.41–0.98). The study concluded that biannual screening reduced HCC mortality by 37%.