Chronic hepatitis B treatment with oral antiviral drugs is a long course. During this course, antiviral resistance is a serious issue, particularly, if genetically low barrier drugs are in use. Host immunity is accepted to have an effect on antiviral resistance development. The earliest clinical sign of drug resistance is virologic breakthrough. In this study, we aimed to investigate the relation between HLA-DQB1 alleles and virologic breakthrough events.The patient records at single institution hepatology clinic were reviewed. Local institution ethics committee approval was taken. The patients' demographic data, virologic parameters, treatment statues were noted. Patients who had received lamivudine or adefovir were recruited and grouped into two according to virologic breakthrough occurrence. Patients who were not compliant to the given treatment were excluded. Blood samples were taken for DNA extraction. HLA-DQB1 alleles were determined at high level by sequence-specific primers-polymerase chain reaction. The distribution of DQB1 alleles among groups was analyzed.One hundred ninety-eight patients were eligible for the study. Ninety-six of them had virologic breakthrough where 102 did not have. DQB1 0503 allele was more frequent in patients without breakthrough (28.4% vs. 12.4%, P=0.006). In univariate analysis, HBeAg seropositivity (P<0.001), absence of cirrhosis (P=0.007), younger age (P=0.002) and higher pretreatment logDNA (P<0.001) were related to breakthrough events. However, in multivariate analysis only logDNA (P<0.001) and DQB1*0503 (P=0.02) allele revealed statistically significant relation with breakthrough events.Host immunity may have an effect on outcome during treatment with oral antiviral drugs. A patient with better immunologic profile may suppress the viral replication better and this may cause less resistance occurrence during treatment with genetically low barrier drugs.