Oral fluoroquinolone prophylaxis during salvage chemotherapy for relapsed/refractory lymphoma is controversial. In this study, we retrospectively evaluated the effect of prophylactic levofloxacin (LVFX) in patients with relapsed/refractory lymphoma who underwent salvage chemotherapy during a recent 11-year period at our hospital. Forty-five patients and 111 cycles of chemotherapy were included in this study. The prophylaxis of LVFX was conducted in 59 cycles (53.2%). The proportion of female patients, relative dose intensity < 1.0, and absolute neutrophil count ≥ 1,500/μL were significantly higher in lymphoma patients without LVFX prophylaxis than in those with LVFX prophylaxis ( p < 0.05). Most patients in these groups received the prophylactic use of Granulocyte Colony Stimulating Factor. The incidence rate of febrile neutropenia (FN) was 51.9% (27 cycles) in the group without prophylaxis and 49.1% (29 cycles) in the LVFX prophylaxis group. The median duration of hospitalization was 22.42 ± 1.39 days in the group without prophylaxis group and 23.07 ± 1.28 days in the group with prophylaxis. There were no statistically significant differences between these groups. Prophylactic LVFX did not contribute to reducing the risk of FN and shortening the hospitalization duration in our patients with relapsed/refractory lymphoma who were receiving salvage chemotherapy.