Background Early diagnosis of sepsis is vital for neutropenic patients with hematologic malignancies. However, finding an early marker is still a challenge. Aim The aim of this study was to assess the utility of midregional fragment of proadrenomedullin (MR-proADM), compared with C-reactive protein (CRP), as an early marker for sepsis in severely neutropenic young patients with hematologic malignancies. Patients and methods A total of 100 severely neutropenic patients with hematologic malignancies, 1–15 years old, admitted to the Pediatric Hematology and Oncology Unit (Zagazig University, Zagazig, Egypt), and developed fever, were randomly recruited. Blood samples, taken on the first day of each febrile episode, were cultured. In addition, on the first and second febrile days, serum CRP and serum MRproADM levels were estimated. Results Patients constituted two groups: a bacteremia/sepsis (BS) group of 36 patients with 47 febrile episodes, and pyrexia of unknown origin (PUO) group of 64 patients with 88 febrile episodes. CRP levels were not statistically different between the BS and PUO groups on either days 1 or 2. However, MRproADM levels were significantly different between the two groups on both days. On receiver operating characteristic curve analysis, CRP was a poor differentiator between BS and PUO. Area under the receiver operating characteristic curve for CRP on days 1 and 2, were 0.509 and 0.529, respectively, whereas MR-proADM had higher discriminatory power from day 1 (area under the curve=0.939). Conclusion This study adds to the recently increasing literature indicating that MR-proADM is a promising early marker for sepsis in severely neutropenic young patients with hematologic malignancies.