Aberrant IgG glycosylation is a feature of hepatitis B virus (HBV) infection but its effect on a long-term efficacy of antiviral therapy has never been addressed. After a screening of 1,085 patients, 132 eligible HBV e antigen (HBeAg)-positive and 101 HBeAg-negative patients with anti-HBV nucleos(t)ide analogue monotherapy were enrolled with on-treatment follow-ups for at least one year. IgG1 N-glycome was profiled using mass spectrometry and evaluated for its relevance in treatment responses. The results indicated that a high level of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) at baseline was associated with the severity of liver inflammation and damage but advanced treatment responses, including HBV DNA loss, HBeAg seroconversion, a reduced drug resistance rate, and a liver histological improvement at year 1, thereby improving the long-term treatment efficacy and the probability of treatment discontinuation in HBeAg-positive patients. Stepwise Cox regression analyses revealed that baseline IgG1-G0F >30% was an independent factor that links to virological response (HR 3.071, 95% CI 1.835-5.141, P < 0.001) or HBeAg seroconversion (HR 2.034, 95% CI 1.011-4.093, P = 0.046). Furthermore, a high IgG1-G0F level at the treatment endpoint was associated with an off-treatment sustained virological response. In conclusion, IgG1-G0F favors the medication outcome for HBeAg-positive chronic hepatitis B.