Background & Aims: Pretreatment predictors of finite nucleo(s)tide analogue (NUC) therapy remain elusive. We studied the association between pretreatment HBV DNA levels and outcomes after therapy cessation., Methods: Patients with chronic hepatitis B who were HBeAg negative at the start of NUC treatment were enrolled from sites in Asia and Europe. We studied the association between pretreatment HBV DNA levels and (1) clinical relapse (defined as HBV DNA >2,000 IU/ml + alanine aminotransferase >2 × the upper limit of normal or retreatment) and (2) HBsAg loss after NUC withdrawal., Results: We enrolled 757 patients, 88% Asian, 57% treated with entecavir, with a median duration of treatment of 159 (IQR 156-262) weeks. Mean pretreatment HBV DNA levels were 5.70 (SD 1.5) log IU/ml and were low (<20,000 IU/ml) in 150 (20%) and high (>20,000 IU/ml) in 607 (80%). The cumulative risk of clinical relapse at 144 weeks after therapy cessation was 22% among patients with pretreatment HBV DNA levels <20,000 IU/ml vs . 60% among patients with pretreatment HBV DNA levels >20,000 IU/ml, whereas the cumulative probabilities of HBsAg loss were 17.5% vs . 5% ( p <0.001). In multivariable analysis, pretreatment HBV DNA levels <20,000 IU/ml were independently associated with a reduced likelihood of clinical relapse (adjusted hazard ratio 0.379, p <0.001) and with an increased chance of HBsAg loss (adjusted hazard ratio 2.872, p <0.001)., Conclusions: Lower pretreatment HBV DNA levels are associated with a lower risk of clinical relapse and a higher chance of HBsAg loss after cessation of NUC therapy, independent of end-of-treatment viral antigen levels. Further studies are needed to confirm these findings in non-Asian populations., Impact and Implications: A subgroup of patients with chronic hepatitis B may not require retreatment after stopping antiviral therapy. In this study, comprising 757 patients with chronic hepatitis B from Europe and Asia, we found that higher viral load before initiation of treatment was a risk factor for relapse after stopping treatment. Patients with a low HBV DNA level before starting antiviral therapy had the lowest risk of relapse, and a high chance of HBsAg loss, after stopping treatment. These findings can help select patients for treatment withdrawal and guide intensity of off-treatment monitoring., Competing Interests: MJS has received speaker’s fees and research support from Roche, Gilead, BMS, and Fujirebio. SMC has nothing to disclose. JYP is an investigator in clinical trials sponsored by AbbVie, Gilead Sciences, Hanmi, and Norvatis. WKS has received speaker’s fees from Mylan and AstraZeneca; has provided consultancy for Abbott; has received speaker’s fees and provided consultancy for AbbVie; and has received speaker’s fees from, provided consultancy for, and received research funding from Gilead Sciences. YT reports lecture fees from Fujirebio, GlaxoSmithKline Pharmaceuticals Ltd, and Gilead Sciences, and research fees from Fujifilm Corp, Janssen Pharmaceutical K.K., Gilead Sciences, GlaxoSmithKline Pharmaceuticals Ltd, Sysmex, and Stanford Junior University. FvB has received research support from and provided consultancy for Roche. TB currently acts as an advisor to AbbVie, Alexion, Bayer, BMS, Gilead, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical. He has received speaking honoraria from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, Janssen, MSD/Merck, Merz, Novartis, Sirtex, and Sequana Medical in the past 2 years. He has received grant support from AbbVie, BMS, Gilead, Humedics, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical. FZ is an advisor for Aicuris, Aligos, Antios, Assembly, Blue Jay, Evotec, Gilead, and GSK, and has received research grants from Assembly, Beam, Janssen, and Viravaxx. SHA has acted as an advisor and investigator for Gilead, Janssen, AbbVie, Roche, Assembly Biosciences, Arbutus, Brii, Vaccitech, GSK, Inovio, Aligos, Vir Biotechnology, SL Vaxigen, GeneOne Life Science, GreenCross, Yuhan, Samil, and Ildong. GND is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, and Sobi; has received research grants from AbbVie and Gilead; and has served as PI in studies for AbbVie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc, Sobi, and Intercept Pharmaceuticals. MB has received fees for consultancy/speakers bureau from AbbVie, Gilead, Janssen, EISAI-MSD, and Roche. HW has received research grants from Abbott, AbbVie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, and Siemens; consultant fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV; and speaker fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV. MC has received personal fees from AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck (MSD), Biogen, Falk Foundation, Boehringer Ingelheim, Siemens, and Spring Bank as well as grants and personal fees from Roche. MFY has provided consultancy for and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myers Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, and Spring Bank Pharmaceuticals, and has received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation. KA has received fees for consultancy/speakers bureau from Assembly, Aligos, Arbutus, Gilead, Immunocore, Janssen, Roche, Sobi, Spring Bank, and Vir, and research support from Abbott, Gilead, and MSD. AB has received research fees from Fujirebio, Gilead Sciences, and Janssen Pharma. MB reports consultancy and lecture honoraria from AbbVie, Arbutus, Gilead, Janssen, Merck/MSD, and Spring Bank. GP has served as an advisor/lecturer for AbbVie, Albireo, Dicerna, Gilead, GSK, Janssen, Ipsen, MSD, Novo Nordisk, Roche, and Takeda, and has received research grants from AbbVie and Gilead. CHC has nothing to disclose. BM has received speaker and/or consulting fees from Abbott Molecular, Astellas, Intercept, Falk, AbbVie, Norgine, Bristol Myers Squibb, Fujirebio, Janssen-Cilag, Merck (MSD), and Roche. He has also received research support from Abbott Molecular, Altona Diagnostics, Fujirebio, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)