Chronic hepatitis B still represents a major challenge for clinicians and the public health service even years after the development of an efﬁcient vaccine and potent antiviral agents. The major actual problems in treating chronic hepatitis B (HBV) patients are represented by the lack of reliable biomarkers which can predict the response to speciﬁc types of therapy. With the availability of different treatment options for chronic HBV patients at our disposal [Pegylated Interferon (pegIFN), Nucleosidic Analogues (NUCs), combined therapies] the results of treatment remain modest. A better selection of patients for each treatment regimen requires an early predictive factor for treatment efﬁciency especially with NUC therapies witch tend to have a very long treatment period (up to ﬁve decades) for reaching HBs clearance. The main objective of our study is to identify the most important predictive factors for early NUC treatment response. We observed that baseline quantitative HBs antigen (qHBsAg) levels, rapid qHBsAg decrease rate in the ﬁrst year of treatment and high ALT levels are important predictors for HBs antigen loss while the decrease rate of HBV-DNA and the treatment regimen are not reliable predictive factors.