The HLA system (human leukocyte antigen) is the major tissue matching system. A key role in immunological processes has HLA molecules and membrane proteins that act as antigens and the foreign organism causing an immune response. Antigens and genes of the HLA system are determined by serological and molecular methods. The microlymphocytotoxicity test is a serological method most commonly used to determine class I and II HLA system antigens. Molecular determination of the HLA gene can be performed using two methods, namely the PCR-SSO method (Polymerase chain reaction Sequence Specific Oligonucleotide), and the other method is PCR-SSP (Polymerase chain reaction - Sequence Specific Primer). Before performing molecular methods, it is necessary to isolate DNA from peripheral blood. The PCR-SSO method is based on the binding of a DNA molecule that has been amplified on a suspension of microspheres. Rheumatoid arthritis is a chronic, severe, autoimmune inflammatory disease whose main feature is synovitis. There is destruction of connective tissue and joint structures which ultimately leads to painful and inflammatory joints with frequent deformities. The aim of this study was to determine the frequency of HLA alleles in subjects suffering from rheumatoid arthritis in the Split-Dalmatia County. Molecular methods prove the connection of a common epitope. The HLA class II molecule was an area of interest because it showed particular susceptibility to disease development. Molecular methods have facilitated the study of these linkages using inherited sequences from the listed amino acids QKRAA, QRRAA or RRRAA found in hypervariable regions as target sites.