Hepatitis B virus (HBV) is an important pathogen responsible for serious diseases like chronic hepatitis, cirrhosis and liver cancer. Turkey is located in the intermediate endemic region based on the average HBV surface antigen positivity. The high replication capacity of HBV and the lack of proofreading activity of the reverse transcriptase (RT) enzyme makes the virus prone to mutations. In this study, S gene mutation which is detected in a chronic HBV case without any follow-up and treatment is presented. Although patient was HBsAg negative and anti-HBs positive in the examinations, the mutation analysis was performed upon the high level of HBV DNA load and sG145R (vaccine escape) mutation in S gene region and rtI169F, rtV173L, rtA181G and rtT184R mutations in pol gene region were detected. S gene region mutations may cause false negatives in diagnostic assays that detect HBsAg. At the same time, it is a public health problem because these HBV variants can also be transmitted by vertical and horizontal routes. Therefore, when atypical serological profiles are encountered, it is of utmost importance to remember S gene mutations and perform necessary analyses.