Immunocompromised patients make up a relatively small but challenging group of patients on PICU, who have significantly increased l morbidity and mortality. There is a wide range of immunocompromised patients on the PICU, ranging from those who have primary immunodeficiency to those who may have secondary immunodeficiency in response to treatment, for example, to oncological disorders or after organ transplantation. Hemophagocytic lymphohistiocytosis (HLH) is a potentially lethal condition characterized by hyperinflammation and organ dysfunction. HLH is a condition that requires a high degree of suspicion for diagnosis, and early treatment is associated with better outcomes. The post-hematopoietic stem cell transplant (HSCT) patients represent a very complex patient cohort, who have a disproportionately high rate of PICU mortality compared to any other patient cohort. The post-HSCT patient is at risk of organ failure due to a number of different complications including sepsis, medication-related complications, and immune-mediated complications. Early recognition, a thorough diagnostic approach and understanding within a multidisciplinary team, is essential to optimize outcomes for this group of patients.