Bortezomib is effective in the therapy of multiple myeloma (MM), but causes infections that are different from those associated with conventional chemotherapy. It is important to identify the risk factors that facilitate infections associated with bortezomib therapy. In the present report, we sought to (1) define the features of the infections associated with this therapy and (2) identify the immune mechanisms responsible for the observed susceptibility to these infections. We first retrospectively analyzed the clinical data of 143 patients who had received bortezomib therapy for MM. We then prospectively assessed the modulation of T lymphocyte status during this therapy, and evaluated potential relationships between infections and T lymphocyte changes. The infection rates peaked during the first cycle of bortezomib therapy (47.6%) in patients with MM (p < 0.05 vs. subsequent cycles). Bortezomib therapy was associated with higher incidence rates of viral and fungal infections (15.8%, p < 0.05 vs. conventional chemotherapy). In addition, patients with the IgG immunophenotype showed higher bacterial and viral infection rates (respectively, p = 0.008 and 0.009). The T lymphocyte numbers significantly decreased after bortezomib therapy (p < 0.05), and the same was true for the Th1/Th2 ratio (p < 0.01). Patients with MM who have decreased lymphocyte counts, while on bortezomib therapy are more likely to develop bacterial or viral infections. In addition, an imbalance in T lymphocyte subsets is also associated with bacterial or viral infections in these patients.