BACKGROUND: Hospitalization for chemotherapy-induced febrile neutropenia is associated with substantial cost and may negatively impact clinical outcome due to associated dose attenuation. METHODS: Medical records of 1355 patients with intermediate-grade non-Hodgkin lymphoma receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or similar chemotherapy were reviewed. The potential risk factors associated with first hospitalization for febrile neutropenia were evaluated. RESULTS: In the current study, 230 patients (17%) experienced 1 or more hospitalizations for febrile neutropenia and greater than one-half of all initial hospitalizations for febrile neutropenia occurred in Cycles 1 or 2. Increased risk of hospitalization for febrile neutropenia, based on Cox proportional hazards models, was significantly associated with the following characteristics: age 65 years or older (hazard ratio [HR] = 1.79; 95% confidence interval [95% CI], 1.35-2.37), serum albumin level at presentation less than or equal to 3.5 g/dL (HR = 1.34; 95% CI, 1.01-1.78), planned average relative dose intensity greater than or equal to 80% (HR = 2.70; 95% CI, 1.47-4.98), baseline absolute neutrophil count less than 1500/mm3 (HR = 1.98; 95% CI, 1.28-3.06), and the presence of hepatic disease (HR = 2.18; 95% CI, 1.11-4.28). Lack of early granulocyte colony-stimulating factor in Cycles 1 and 2 was also associated with increased risk of hospitalization for febrile neutropenia, but this did not reach statistical significance. A composite risk score based on these potential risk factors effectively distinguished patients at greater risk of hospitalization for febrile neutropenia (P < 0.001), the majority of which were observed during the first cycle of chemotherapy. CONCLUSIONS: The data from the current study demonstrated that the risk of initial hospitalization for febrile neutropenia occured early in the course of CHOP-like chemotherapy. Identified risk factors for febrile neutropenia hospitalization may facilitate the use of targeted supportive care.