Genetic, immunological and environmental factors are involved in the pathogenesis of the gastrointestinal diseases. Situated on the short arm of the chromosome 6, the HLA system is very polymorphic and has the capacity to confer susceptibility or resistance to different diseases. The relationship HLA vs. disease differs with the disease and, sometimes, with the ethnic-racial group studied. Histocompatibility molecules could determine the age of onset, the treatment response and the clinical course for some diseases. The recent discovery of new methods to typify HLA alleles and the changes in its nomenclature has contributed to a better understanding of this system. Nevertheless, has not thoroughly widespread. The aim of this review is to discuss the HLA structure and function, methods of detection, nomenclature and its association with celiac disease, Crohn's disease, autoimmune hepatitis, autoimmune pancreatitis and oral recurrent ulcers.