The utility, efficacy and cost-effectiveness of establishing a prospective screening program for hepatocellular carcinoma (HCC) in a low-cost setting as Egypt has not been previously studied. Eligible patients in this observational study were screened by ultrasound and alpha-fetoprotein (AFP) every 6 months. A focal lesion on ultrasound or AFP >200 ng/ml or significant increase in 6 months indicated a recall. Characteristics of cases detected on screening were compared to patients diagnosed outside the screening program. Of 1,920 eligible patients, 1,286 patients participated and 102 patients (7.9 %) developed HCC, with an annual incidence of 5.3 %. Ninety-one (89.2 %) were BCLC stage 0 or A and 11 (10.8 %) stage D. Ultrasound detected a hepatic focal lesion in 99 patients, of which 74 were confirmed to be HCC, and AFP added another 28 HCC cases. The annual cost of detecting a treatable HCC case by ultrasound was 3,980 EGP (<euro> 400) and by both ultrasound and AFP 4,645 EGP (<euro> 500). Adding the cost of treatment, the cost/quality-adjusted life year (QALY) gained was 7,907 EGP (<euro> 800)/QALY for screening with ultrasound only, and 8,430 EGP (<euro> 850)/QALY for using both ultrasound and AFP, which in both cases is <50 % of the per capita GDP and <20 % of the accepted cost/QALY for Egypt. Screening for HCC is feasible and is highly cost-effective in a resource-limited setting. Adding AFP to ultrasound increased detection with a trivial addition to cost/QALY.