A randomized controlled trial was conducted to assess the effect of biannual screening with 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 (HBV) infection or a history of chronic hepatitis. Participants were randomly assigned to a screening group (9,373) or control group (9,443). The screening group underwent AFP tests and ultrasonography every 6 months, while the control group received no screening. Screening was stopped in December 1997, and all participants were followed up until December 1998. The primary outcome was HCC mortality. The screening group completed 58.2% of the offered screening. The number of HCC cases was 86 in the screening group versus 67 in the control group. Subclinical HCC was 52 (60.5%) versus 0 in the screening group versus control group. Small HCC was 39 (45.3%) versus 0. Resection was achieved in 40 (46.5%) versus 5 (7.5%). The 1-, 3-, and 5-year survival rates were 65.9%, 52.6%, 46.4% versus 31.2%, 7.2%, 0. Thirty-two people died from HCC in the screening group versus 54 in the control group. The HCC mortality rate was significantly lower in the screening group (83.2/100,000) than in 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%. The study found that periodic screening results in a significant shift to an earlier stage of HCC, leading to improved survival. The study was approved by the Fudan Medical School Ethics Committee. The validity of the screening tests was reported elsewhere. When AFP and ultrasonography were used in parallel, the detection rate, false positive, and positive predictive values were 92%, 7.5%, and 3.0%, respectively. The study demonstrated that biannual screening with AFP and ultrasonography significantly reduced HCC mortality in people at increased risk.A randomized controlled trial was conducted to assess the effect of biannual screening with 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 (HBV) infection or a history of chronic hepatitis. Participants were randomly assigned to a screening group (9,373) or control group (9,443). The screening group underwent AFP tests and ultrasonography every 6 months, while the control group received no screening. Screening was stopped in December 1997, and all participants were followed up until December 1998. The primary outcome was HCC mortality. The screening group completed 58.2% of the offered screening. The number of HCC cases was 86 in the screening group versus 67 in the control group. Subclinical HCC was 52 (60.5%) versus 0 in the screening group versus control group. Small HCC was 39 (45.3%) versus 0. Resection was achieved in 40 (46.5%) versus 5 (7.5%). The 1-, 3-, and 5-year survival rates were 65.9%, 52.6%, 46.4% versus 31.2%, 7.2%, 0. Thirty-two people died from HCC in the screening group versus 54 in the control group. The HCC mortality rate was significantly lower in the screening group (83.2/100,000) than in 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%. The study found that periodic screening results in a significant shift to an earlier stage of HCC, leading to improved survival. The study was approved by the Fudan Medical School Ethics Committee. The validity of the screening tests was reported elsewhere. When AFP and ultrasonography were used in parallel, the detection rate, false positive, and positive predictive values were 92%, 7.5%, and 3.0%, respectively. The study demonstrated that biannual screening with AFP and ultrasonography significantly reduced HCC mortality in people at increased risk.