Infection with hepatitis B virus (HBV) is a major problem worldwide. The major histocompatibility complex plays an essential role in host immunity and can help eliminate the HBV of infected hepatocytes. Our study aimed to determine the role of certain human leukocyte antigen (HLA) class II molecules (i.e. HLA-DRB1 and HLA-DQB1) in the persistence or removal of HBV. Sixty patients confirmed to be HBV-positive via real-time polymerase chain reaction (PCR), i.e. people with chronic active hepatitis, were included in the study along with a control group of 100 healthy individuals without evidence of HBV infection. The DNA was subsequently used to determine HLA-DRB1 and HLA-DQB1 low-resolution typing genetic profile via PCR amplification. The univariate analysis performed revealed significant association of the HLA-DRB1*03 and HLA-DQB1*05 alleles to the infected persons (study group), while HLA-DRB1*01 was shown to be protective against HBV infection. To our knowledge, this is the first Romanian study associating HLA with HBV, and it can provide valuable insight concerning the relationship between genetic factors and immune response in the sampled population.