Recent advances in febrile neutropenia have highlighted the value of risk stratification especially that it can have important implications in terms of management. We aimed to identify a serum marker that may help to stratify febrile neutropenic pediatric patients treated for hematologic malignancies at the time of first evaluation. Thus, C-reactive protein (CRP), interleukin-8 (IL-8), and monocyte chemotactic protein-1-alpha (MCP-1-alpha) were evaluated for their predictive and diagnostic relevance in febrile episodes of cancer patients. Within 24 hours of fever, CRP, IL-8, and MCP-1 serum levels were measured and the levels of these markers were related to the clinical findings of the patients. For this purpose, we collected and analyzed clinical data of 85 fever episodes occurring in 76 patients with hematologic malignancies, presenting to the Department of Pediatric Oncology, National Cancer Institute, Cairo University, during a 6-month period. Neutropenic children with febrile episodes were classified into 2 groups, a group with unexplainable fever (group I, n=26) and another group with either blood culture positive, and/or fever periods with a documented clinical sepsis and/or local infection (group II, n=59). Clinically, local sites of infection were encountered in 39 cases (45.9%), whereas a positive blood culture was detected in 20 cases. CRP, IL-8, and MCP-1 levels were significantly lower in group I versus group II (P value <0.001). There were overlaps of values between groups. CRP > or =90 mg/L was significantly associated with chemotherapy-related neutropenia and fever owing to bacteremia (P=0.038). The sensitivity, specificity, negative and positive predictive values of CRP, MCP-1, and IL-8 were (70%, 73%, 51%, and 85%), (64%, 92%, 53%, and 95%), and (71%, 77%, 54%, and 88%), respectively. Combining 2 or 3 markers improved the diagnostic performance of these test, as 78% of group II had elevated 2 or 3 markers versus 16% of the group with no evident infection. Low levels of CRP, MCP-1, and IL-8 could identify patients with unexplainable fever; whereas, high levels of these markers were of help in the diagnosis of infectious episodes. A model combining more than 1 marker is recommended in the assessment of febrile neutropenia.