Background: Loss of hepatitis B surface antigen (HBsAg) in chronic hepatitis B (CHB) infection is a favorable outcome. Type I interferon (IFNI) has an essential role to fight virus infections when they bind to the IFN-α/β receptor (IFNAR). Free-circulating IFNARs, known as IFNAR2, perform as carrier proteins to keep the ligands from proteolysis as well as antagonists for ligand binding. Objectives: In this study, we evaluated the HBsAg titer and IFNAR2 in serum baseline of a subcohort of Iranian HBeAg-negative patients with chronic hepatitis B. Methods: Sixty-four patients who spontaneously cleared HBsAg and 100 chronic hepatitis B patients enrolled in this study for assessment of the serum levels of HBsAg and IFNAR2. Results: Serum levels of HBsAg and IFNAR2 were both powerfully associated with loss of HBsAg. The baseline HBsAg titer was significantly lower (333.72 ± 1300 IU/mL vs 3811 ± 6779 IU/mL, P = 0.00) and the IFNAR2 serum level was significantly higher (1.64 ± 0.6 vs 0.87 ± 0.5 ng/mL, P = 0.00) in those who cleared HBsAg compared to the CHB patients. Conclusions: These findings indicated the association of the HBsAg titer and serum IFNAR2 in HBsAg clearance in hepatitis B virus-infected patients. In consequence, immune mechanisms related to IFN-α/β signaling might be responsible in CHB outcome. © 2017, Ahvaz Jundishapur University of Medical Sciences.