Screening is the only practical approach for improving the management of hepatocellular carcinoma (HCC) patients, as early detection increases the application of curative treatments. A conference of experts from Japan, USA, and Europe (Barcelona 2005) advised surveillance every six months for patients with chronic liver disease at increased risk of HCC with abdominal US. Whether this approach benefits HCC patients in terms of survival is still uncertain, since available data are retrospective and biased by lead-time factors in the calculation of patient survival. Only one randomized controlled study in China showed the benefit of surveillance for HCC; however, in a population-based setting. Today, clinic-based, randomized studies are unfeasible for ethical reasons. In a cohort of 447 Italian patients with compensated cirrhosis, we compared the survival of HCC patients identified along three consecutive quinquennia of surveillance. HCC developed in 112 patients (3.4% per year) and was the prime cause of death. Forty-six patients (41%) had a single tumor with mean sizes of 3.7, 3.0, and 2.2 cm in the three quinquennia (first vs third, P = 0.0147; second vs third, P = 0.02) and 38(44%) underwent radical therapies. Mortality rates in HCC patients fell from 45% in the first quinquennium to 10% in the third (P = 0.0009), in parallel with a reduction in mortality of treated patients (34, 28, and 5%) (first vs third, P = 0.0024). Cirrhotic patients developing HCC during the last five years of surveillance survived longer than previously, as a consequence of improved management of the tumor and complications of cirrhosis. It remains controversial whether HCC screening is cost-effective, i.e. whether the cost of detection, confirmatory studies, and treatment are outbalanced by the number of life-years gained. In a retrospective study of Italian patients with cirrhosis, there was an incremental cost-efficacy ratio of surveillance vs no surveillance to be $USD 112 993 per liver-year saved. The cost of surveillance was increased by surgery applied to 15 patients with HCC detected during surveillance.