While vaccination programs have reduced the incidence of severe infections in children, severe childhood infections remain an important cause of illness and death worldwide. The immune system, also known as our defense system, plays a critical role in protecting us against pathogens such as bacteria and viruses. Defects in any part of this complex system can have serious consequences for the individual. Since the second half of the 20th century, there has been more focus on how defects in the immune system make people more likely to experience severe infections. Primary immunodeficiency diseases (PIDs) refer to a group of disorders caused by defects in the immune system that are presented from birth, often due to changes in genes that control the immune system. People born with a PID have an error in their immune system, causing increased susceptibility for invasive and/or recurrent infections. There is a critical need to understand the relationship between PIDs and severe childhood infections. Therefore, this study focuses on understanding the prevalence, clinical symptoms and underlying genetic variants of PID in children with severe viral or bacterial infections. Building on similar studies conducted in France, Switzerland, and the UK, this Belgian prospective, single-center study had the aim to screen children with severe infections at the pediatric intensive care unit (PICU) of UZ Ghent. Unlike other studies that often focused on specific diseases or pathogens, this research included all children admitted to the PICU with severe bacterial or viral infection. The proposed screening involved blood samples from the patients for immunological analysis. Additionally, patient data (such as patient and pathogen characteristics, warning signs for PID, medical history, length of hospital stay…) were collected. Eventually, based on the immunological results and data, genetic testing was sometimes requested to detect a genetic error leading to the PID. Results of this immunological and genetic testing showed that a substantial proportion (28%) of the children admitted to the PICU with a severe infection has a confirmed underlying primary immunodeficiency, with an additional 25% showing probable PID. These findings underscore the importance of screening for PID in this population. Over 480 types of primary immunodeficiency are recognized, and this number continues to grow. The general prevalence of PID is approximately 1 in 10 000, while certain conditions such IgA deficiency, have an estimated prevalence of 1 in 500 individuals. This means that some PIDs are more common than previously thought and its prevalence will only increase with the ongoing discoveries of newly defined PIDs. While some of the most common primary immunodeficiencies only cause mild symptoms and do not significantly increase the risk of severe infections, others can lead to severe, life-threatening infections with severe consequences. Early detection of the underlying immune disorders in these patients is essential, as early intervention can improve the quality of life for the affected children. It may lead to specific prevention strategies to avoid recurrent infections and/or irreversible organ damage. Furthermore, identifying the underlying genetic defect enables the possibility of genetic counseling, which makes informed decision making for the parents’ next pregnancy possible.