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Background: Because of the known limitations of ultrasonography (US) alone, we reevaluated whether complimentary testing for serum alpha-fetoprotein (AFP) is helpful in surveilling for hepatocellular carcinoma (HCC) in high-risk populations. Methods: We included, from a hospital-based cancer registry, 1,776 asymptomatic adults who were surveilled biannually with the AFP test and US and eventually diagnosed with HCC between 2007 and 2015. Based on the screening results, these patients were divided into three groups: AFP (positive for AFP only; n ¼ 298 [16.8%]), US (positive for US only;n¼978 [55.0%]), and AFPþUS (positive for both; n ¼ 500 [28.2%]). We compared the outcomes of the three groups, calculating the survival of the AFP group both as observed survival and as survival corrected for lead-time.Results: In terms of tumor-related factors, the separate AFP and US groups were more likely to have early stage HCC and to receive curative treatments than the combined AFPþUS group (Ps < 0.05). The AFP group had significantly better overall and cancerspecific survival than the AFPþUS group after adjusting for covariates (adjusted hazard ratios [HRs] 0.68 and 0.62, respectively). In analyses correcting for lead-time in the AFP group (doubling time 120 days), the respective adjusted HRs for the AFP group were unchanged (0.74 and 0.67), but they were no longer significant after additional adjustment for tumor stage and curative treatment (0.87 and 0.81). Conclusions: HCC cases detected by the AFP test without abnormal ultrasonic findings appear to have better survival, possibly as a result of stage migration and the resulting cures. Complementary AFP surveillance, together with US, could be helpful for at-risk patients.Legal entity responsible for the study: Ju Hyun Shim.