Spontaneous HBsAg seroclearance has been mainly studied in populations from Asia, Australia, the Pacific Islands, and Polynesia. For the first time, we evaluated the spontaneous HBsAg seroclearance and its possible associated factors and the risk of disease progression in HBeAg-negative patients with inactive infection all coming from the same region in South Italy. In this multicenter retrospective study, 146 patients were selected after 18 months of observation and followed for a median of 82 months (IQR 60–107). For our analyses, they were divided into three groups based on their HBsAg levels: <100 IU/mL, 100–1000 IU/mL, and >1000 IU/mL. Crude and adjusted hazard ratios (HRs) for HBsAg seroclearance were determined. During the follow-up period, three patients (2.0%) showed a disease progression with an increased liver stiffness, whereas 17 (11.6%) cleared the HBsAg. Patients with HBsAg levels <100 IU/mL had the highest probability of HBsAg seroclearance compared to the other two groups (p = 0.009). In the multivariate analysis, the HBsAg level <100 IU/mL was the only parameter independently associated with HBsAg seroclearance (adjusted HR = 3.53; CI 1.29–9.69; p = 0.01). In patients with chronic HBV inactive infection, HBsAg levels <100 IU/mL predicted the highest probability of HBsAg seroclearance.