Bortezomib is a proteasome inhibitor with potent antimyeloma activity in relapsed/refractory multiple myeloma (MM) patients. We evaluated the types and factors affecting the onset of infectious complications and mortality owing to infection in MM patients treated with bortezomib-based regimens. We reviewed 139 patients with MM treated with regimens containing bortezomib in order to assess the types and factors affecting the development of severe infections. Infections occurred in 56 (40.3 %) of 139 patients and 83 (7.8 %) cases of the 1,069 evaluable cycles. Severe infections developed in 43 (30.9 %) patients and ten patients (7.1 %) died during bortezomib-based treatment. Multivariate analysis determined lymphocytopenia grade 3-4 (OR 3.17, 95 % CI 1.38-7.31, P = 0.007) and number of cycles ≤ 8 (OR 3.91, 95 % CI 1.39-11.02, P = 0.010) as risk factors associated with increased severe infection. This study showed that MM patients who received bortezomib-based regimens are at a higher risk of severe infections within eight cycles of treatment during especially severe lymphocytopenic periods. MM patients treated with bortezomib-based regimens should be closely monitored for the development of infectious complications during lymphocytopenia.