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There is an urgent need for new high‐quality markers for the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2‐bound α1‐acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2‐bound AGP in the early detection of HCC. In a retrospective case–control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct‐acting antiviral agents (n = 93), we measured S2‐bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow‐up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty‐one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction‐associated steatotic liver disease and HCC of different etiologies were analysed. S2‐bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2‐bound AGP for the early detection of HCC during treatment and follow‐up. Interestingly, S2‐bound AGP levels correlated with aspartate aminotransferase (ρ =.56, p = 9.5×10−15) and liver elastography (ρ =.67, p = 2.2×10−16). Of note, S2‐bound AGP decreased in patients chronically infected with HCV after treatment‐induced HCV clearance. Fucosylated S2‐bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2‐bound AGP as a novel tumour marker requires further investigation. [ABSTRACT FROM AUTHOR]