Fluoroquinolone is recommended as a prophylactic antibiotic for high-risk patients with profound neutropenia. We previously reported that multiple myeloma (MM) patients who received bortezomib-based regimens were at higher risk of severe infections (30.9 %) associated with lymphocytopenia. In the study, we evaluated whether severe infectious complications can be prevented by prophylactic administration of oral levofloxacin in MM patients treated with bortezomib-based regimens. A total of 80 patients received oral levofloxacin 500 mg daily during the median four cycles of treatment. The prophylactic group (n = 80) with levofloxacin showed significantly decreased severe infections compared to a historical control group (n = 139) without levofloxacin prophylaxis during treatment of bortezomib-based regimens (17.5 vs. 30.9 %, P = 0.037). In the prophylactic group, two patients (2.5 %) died of pneumonia and septic shock. Four patients (5 %) stopped levofloxacin due to side effects that consisted of gastrointestinal discomfort (2.5 %), itching sense (1.25 %), and QTc prolongation (1.25 %). In conclusion, prophylaxis with levofloxacin may be effective in the prevention of severeinfection in MM patients receiving bortezomib-based regimens. A prospective randomized study is needed to test the prophylactic effect of levofloxacin in MM patients treated with bortezomib-based regimens.