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Nucleos(t)ide analog (NA) therapy suppresses hepatitis B virus (HBV) DNA, but residual hepatocellular carcinoma (HCC) risk persists. O-glycosylated hepatitis B surface antigen glycan isomer (HBsAgGi) uniquely reflects virion burden. We evaluated the impact of tenofovir alafenamide (TAF) versus entecavir (ETV) on 48-week HBsAgGi kinetics and its utility in stratifying HCC risk in 90 NA-naïve patients (ETV: 73; TAF: 17). A favourable response was defined as a reduction or maintenance of low HBsAgGi levels. TAF independently predicted a favourable response compared with ETV (penalised odds ratio 3.60, p = 0.030). A significant interaction occurred between HBeAg status and HBsAgGi response in relation to HCC development (p = 0.038). In HBeAg-positive patients, a poor response was associated with increased HCC risk (hazard ratio 7.34, 95% confidence interval [CI] 1.96-20.35, p = 0.001); however, the exact magnitude warrants cautious interpretation due to wide CIs. This association was absent in HBeAg-negative cases. Adding HBsAgGi response to the aMAP score improved long-term HCC prediction exclusively in the HBeAg-positive cohort. As the assay targets genotype C-specific O-glycosylation, the findings cannot be generalised to genotypes A, B, or D. In conclusion, on-treatment HBsAgGi response is a specific surrogate marker for stratifying residual HCC risk in HBeAg-positive patients, and TAF is more effective than ETV in inducing these favourable kinetics.