The HLA system is the most complex genetic system in humans. Among other things, the peculiarities of this system are its pronounced polymorphism, as well as the connection of this system with diseases, which is of great importance in the diagnosis of autoimmune diseases as well as neurological diseases. Migraine is a recurrent, moderately severe to very severe headache lasting between 4 and 72 hours if left untreated. There are several risk factors associated with developing migraines. Immutable factors include genetics, age and gender. The objective of this work was to determine the representation of alleles of the HLA system in patients suffering from migraines and severe headaches in the Split-Dalmatia County, as well as to show the representation of individual alleles of the HLA locus - DRB1*. In subjects with migraine and severe headaches who had HLA-DRB1*16, the representation of genders shows that the percentage of patients is significantly higher in women (68.96%) compared to men (31.04%). The largest number of respondents was in the age group of 46 to 65 years. Antigens and alleles of the HLA system for the purposes of this study were determined by serological and molecular methods. Antigens of the HLA system are determined by the microlymphocytotoxicity test (MLCT), while the PCR-SSO and PCR-SSP were used for the molecular determination of alleles of the HLA system locus. . By determining the alleles of the HLA-DRB1 locus in the group of subjects with migraine, 14 different alleles were observed, of which the highest prevalence is HLA-DRB1*16 (19.59%) and HLA-DRB1*11,-13,-15 with a frequency of 10 , 14%. Compared to the control group, the frequency of alleles HLA-DRB1*16 (19.59% vs 9.60%, p=0.0063) and HLA-DRB1*10 (2.7% vs 0%, p =0.0327) statistically significantly increased in the group of patients with migraine or severe headache. Since alleles of the HLA class I locus (HLA-A, HLA-B) were also determined for diagnostic purposes in our subjects, the analysis revealed a statistically significant association of the HLAB*57 allele in patients with migraine and severe headaches compared to the healthy control group examinee. In order to talk with certainty about the connection between migraine and severe headaches and the HLA-DRB1*16 allele and other alleles of the HLA system locus (HLA-A, HLA-B), it is certainly necessary to expand the study to a larger number of subjects.