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Monotherapy for empirical treatment of febrile neutropenia is effective and often less costly than combination therapy but remains controversial. The controversy results from observations that combination therapy for Pseudomonas aeruginosa improved outcomes, and this approach became a standard. Many subsequent publications, including the Infectious Diseases Society of America guidelines for febrile neutropenia, now support monotherapy. However, changes in the pathogens involved in febrile neutropenia and in their resistance prompt a reevaluation. In the evaluation of new antibiotics, recent trials comparing either cefepime or meropenem with combination therapy or with ceftazidime confirm that monotherapy remains a viable therapeutic approach, with infectious mortality in the 5% range in all arms. The choice of monotherapy should, however, be made on the basis of resistance patterns seen in an institution. The agent selected should be very active against the organisms that are likely to cause rapidly fatal infections, and clinicians must be prepared to modify monotherapy as appropriate.