Background and Objective: The empirical administration of a broad-spectrum β-lactam antibiotic, either as monotherapy or in combination with an aminoglycoside, is an essential component of the initial management of patients with fever and severe neutropenia. Multiple antibiotics have been tested for this indication. Cefepime is a fourth-generation cephalosporin with in vitro activity against most gram-negative and many gram-positive bacteria. We have studied the use of this agent as monotherapy in this indication. Methods: One hundred and twenty-six episodes of febrile neutropenia in 98 adults with hematological malignancies were treated with cefepime monotherapy. Cefepime was given at a dose of 2 g every 8 h i.v. Most episodes (49%) were fever of unexplained origin, while a microbiologically documented and clinically documented infection occurred in 25% episodes each. Seventy-six (61%) episodes occurred after conventional chemotherapy, while 51 (41%) after a hematopoietic stem cell transplantation. Results: Twelve episodes (10%) were not evaluable for response. Among the 114 evaluable episodes, 69 (55% of the initial sample and 61% of those evaluable) responded to cefepime monotherapy, while therapy failed in 45 cases (36% of the initial sample and 39% of those evaluable), including 14 cases who developed breakthrough bacteremia during therapy. There were no deaths due to bacterial infection. At the end of all antibiotic therapy (final outcome) 69 episodes were cured only with monotherapy, 47 were cured with modification of therapy and 10 patients died from an unrelated cause. The only variable that appeared to correlate with response to therapy was the duration of neutropenia, which was longer among patients who failed or developed breakthrough bacteremia than among those who responded to monotherapy. Interpretation and Conclusions: Initial empirical antibiotic therapy with cefepime as a single agent in patients with febrile neutropenia and a hematological malignancy is effective, but patients with prolonged neutropenia appear to be at higher risk for failure. However, with appropriate therapeutic changes the risk of dying from a bacterial infection is very low.