Preventing bacterial infections by prescribing prophylactic antibiotics is seen by many as an important strategy for decreasing infectious mortality in the most profoundly immunosuppressed patients with hematologic malignancies. Comparative studies show consistently that neutropenic patients treated with prophylactic fluoroquinolone antibiotics develop fewer bacteremias than patients treated with placebo or less-potent antibacterials. However, these same studies fail to show increased survival rates in fluoroquinolone-treated patients. This repeated observation is the basis for the continued controversy concerning universal antibacterial prophylaxis of neutropenic patients, namely, the inability to translate the observed reduction in culture-proven bacterial infections with prophylaxis into improved clinical outcomes. The answer to this controversy lies in the effectiveness of empiric antibacterial therapy in response to neutropenic fevers. Mortality from bacterial infections is 1% or less for patients enrolled in empiric treatment trials who do not receive prophylactic antibacterials. Therefore, routine fluoroquinolone prophylaxis offers essentially no potential survival benefit to neutropenic patients with hematologic malignancies. In fact, the increasing potential for fluoroquinolones to select for resistant bacterial pathogens should give pause to the practice of routine prophylaxis of neutropenic patients.