We performed a pilot study on 13 heavily treated hematologic patients, in whom a systemic broad-spectrum antimicrobial prophylaxis was started after the end of the antineoplastic treatment. Results were compared to a historical control group of patients with similar characteristics, in whom antibody were started at the appearance of fever. We observed a remarkable reduction in infectious fevers (1 versus 7, p = 0.03) and a disappearance of bacterial sepsis (0 versus 7, p = 0.005). The length of treatment was longer (18.6 versus 12.0 days, p = 0.06); no side effects were seen. We conclude that this seems to be a promising and safe approach, whose role in the management of selected neutropenic patients could be evaluated with further, wider studies.