Exocrine pancreatic insufficiency (EPI) is suspected but remains understudied in immunosuppressed conditions such as post-hematopoietic stem cell transplantation (HSCT). This prospective observational study aimed to investigate the incidence, impact, and risk factors of EPI in a cohort of 83 pediatric and young adult patients who underwent allogeneic HSCT at Charité - Universitätsmedizin Berlin between 2020 and 2023. Fecal pancreatic elastase (PE) measurements and transabdominal ultrasound were utilized to evaluate pancreatic function over a one-year period. Secondary analysis explored the association of EPI with clinical complications and included a multivariable regression analysis of potential risk factors. Low PE levels significantly correlated with pathological pancreatic imaging findings, independent of concurrent diarrhea. EPI was suspected in 45% (32/71) of patients (95%CI: [34.1%, 56.6%]), with 29% (13/45) (95%CI: [17.7%, 43.4%]) showing signs of prolonged EPI (pEPI) lasting at least 8 weeks. After excluding cases with confounding factors such as missing enteral nutrition and diarrhea, the cumulative incidence of prolonged EPI was 20% (8/41) (95%CI: 10.2%-34.0%) in the overall cohort. EPI was associated with weight loss, prolonged dependence on parenteral nutrition, and extended hospitalizations. Adenovirus (ADV) infection emerged as a significant risk factor for EPI (hazard ratio 3.22 [95%CI:1.26-8.2], p = 0.014), along with additional factors such as higher BMI pre-HSCT, pre-existing pancreatic damage and early post-HSCT fasting. The persistence of pancreatic atrophy and EPI beyond two years post-HSCT in individual cases suggests a potential for permanent pancreatic damage. This study underscores that EPI is a common complication following HSCT, with ADV infection being an important risk factor. The findings support routine PE measurements and early initiation of pancreatic enzyme replacement therapy (PERT), alongside aggressive treatment of ADV infections. Further research is necessary to evaluate the effects of PERT in this population and to explore the applicability of these findings in other immunosuppressed groups.