In order to optimize the clinical management of fever in acute myelocytic leukemia (AML), our experience with febrile patients during two therapy periods was reviewed. A structured approach to the management of fever was then devised and evaluated during a third period. Among a total of 104 patients with AML, 77 were febrile at presentation. Only agranulocytic patients (15%) had severe infection, while 43% had localized sites which responded to specific antibiotic therapy. The remainder (42%) had fever functionally attributed to leukemia. In contrast, life-threatening infection occurred in most patients (90%) after antileukemic treatment was begun. During the trial therapy period, the empiric use of carbenicillin-gentamicin for fever greater than or equal to 101 degree F during aplasia reduced the incidence of sepsis from 90 to 30% and of bacteremia from 50 to 23%. The fall in the incidence of blood and localized site cultures positive for Pseudomonas aeruginosa from 65 to 15% corresponded to a reduction in the number of distinct organisms per site from 1.6 to 1.0. These data suggest that hematogenously born invasion of infected sites by endogenous organisms has been prevented. Aplastic patients with fever responded to therapy by defervescing (54%) or improving clinically (34%). Stopping antibiotics once started while evaluating persistent fever was detrimental. Although the early empiric use of amphotericin B reduced the incidence of fungemia, its proper use in fever management is yet to be determined.