To analyse the impact of intensified prophylaxis with ofloxacin plus rifampin (O+R) in neutropenic patients we used this combination in 40 consecutive cycles of ifosfamide, cytarabine, prednisolone and etoposide (IAPVP-16). This salvage chemotherapy regimen for lymphoma usually produces four to six days of severe neutropenia without significant extrahematologic toxicities. We compared the infectious morbidity during neutropenia under O+R with 58 consecutives cycles using either norfloxacin or no prophylaxis (control group). Fifty-three percent of control group patients and 20% of the O+R group developed febrile neutropenia that required hospital admission (p<0.001, 95% CI for the difference between both proportions of 16% to 51%). Bacteremia was documented in two patients in the O+R group and six in the control group (p=0.08). Gram-positive cocci (GPC) accounted for all six bacteremias in the control group, while both cases in O+R group were due to a quinolone-resistant gram-negative bacteria (GNB) (p<0.01 for GPC). Five patients (13%) who received O+R and 23 (40%) in control group developed fever of unknown origin, p<0.001, while the total duration of hospitalization due to febril neutropenia was 42 days and 158 days, respectively (p<0.001). In conclusion, intensified prophylaxis with O+R appears to reduce the rate of febrile neutropenia and GPC bacteremia in patients with short and severe neutropenia, which translates into a reduction in the need for hospitalization.