Background <p>Data directly comparing the efficacy of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) in combination with peginterferon alfa (PEG-IFNα) for functional cure in chronic hepatitis B (CHB) remain scarce. This study aimed to compare the functional cure rates between these two combination regimens in HBeAg-negative CHB patients.</p> Methods <p>A total of 442 HBeAg-negative CHB patients (ETV group 238 and TDF group 204) with HBsAg levels below 1500 IU/mL were included. All patients received PEG-IFNα-2b once a week based on the chronic administration of ETV or TDF. Study endpoint was functional cure of the patients. Propensity Score Matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used in our study.</p> Results <p>HBsAg levels declined significantly throughout the treatment in both groups. In the original cohort, the TDF group exhibited a higher functional cure rate at week 48 compared to the ETV group (35.78% vs. 25.63%, <i>p</i> = 0.021). However, this difference was abolished after PSM (<i>p</i> = 0.445) and IPTW adjustment (<i>p</i> = 0.336), demonstrating no significant disparity between the regimens. Multivariable analysis identified younger age and lower baseline HBsAg levels as independent favorable factors for functional cure, while the choice of NA (TDF vs. ETV) was not a significant predictor.</p> Conclusions <p>This study has demonstrated that in HBeAg-negative CHB patients with low HBsAg levels, the combination of PEG-IFNα-2b with either TDF or ETV leads to comparable rates of functional cure. Younger age and lower baseline HBsAg level are favorable factors for treatment effect, but not TDF or ETV.</p> Trial registration <p>ChiCTR number: ChiCTR1800020369 (2018-12-25).</p>