Introduction. Primary immunodeficiencies (PIDs) have become a major problem for public medicine, given their complexity and variability, manifested by diagnostic difficulties and the increase in the prevalence of diseases falling under this definition (infections, autoinflammatory diseases, autoimmunity, allergy, malignancies). As part of the scientific research, carried out in USMF „N. Testemițanu” by the collaborators of the Laboratory of Immunology and the Department of Pediatrics, two projects were carried out, including the State Project 2020-2023, the objective of the study of which was the epidemiological and clinical peculiarities with the development and implementation of new methods and operations for the performance of diagnostic and curative management in Republic of Moldova. Material and methods. In the study we implemented a rigorous selection process with a detailed investigation using traditional and contemporary methods to evaluate 984 patients with suspected IDP. We have developed an innovative diagnostic framework, based on international methods (lymphocyte immunophenotyping, latest generation molecular-genetic testing - NGS, assessment of naïve T- and B-lymphocytes, etc.). Results. In the first step, as a guideline, we used the IDP suggestive signs for children and adults, developed by JMF (USA), which showed support for the suspicion of MID and required immunological and genetic confirmation. Among the clinical laboratory tests, the hemogram performed is of essential value (lymphopenia - < 1500 cells/mcl, thrombocytopenia - small platelets, < 70x109/L, leukopenia, eosinophilia) and are important indicators in assessing the patient’s condition, but require interpretation in the context of clinical manifestations. Testing of cellular, uroral and non-specific immune factors allowed identification of the altered immune chain. It is important to mention an essential peculiarity of the immune system factors of potentiation of the altered chain in the realization of defense measures. A novel approach in the early detection of IDP occurred when the study implemented molecular-genetic research of 575 genes, possibly involved in the genesis of MID, using NGS technology with variant interpretation in accordance with the Guidelines of the American College of Medical Genetics. Neonatal screening for IDP represents another key insight in the early identification of asymptomatic infants with a wide range of severe diseases, where early diagnosis and intervention can prevent consequences with significant curative effects.