Current treatments for non-Hodgkin lymphomas are not optimally effective. Among new agents, bortezomib seems to play a pivotal role in the regulation of several cell pathways involved in the development of lymphomas. After results were obtained with clinical trials, we aimed to observe treatment with bortezomib in everyday clinical practice. We performed a multicenter retrospective analysis to assess the efficacy of bortezomib in heavily pretreated (median number of previous therapies 4, range 2–6) lymphoma patients in an off-label setting. Bortezomib therapy was scheduled for 4–6 cycles (1.3 mg/m2 biweekly). Data from 50 patients were collected: 22% had a complete remission, 26% obtained a partial response and the remaining 52% was non-responder. According to histotype, we observed an overall response rate (ORR) of 51.6% in mantle cell lymphomas, an ORR of 60% among follicular lymphoma patients, and an ORR of 50% in the indolent nonfollicular lymphomas. None of diffuse large B-cell lymphoma patients obtained a response. Extra-hematological toxicity was really mild, and peripheral neuropathy occurred in only 5 patients; hematological toxicity was grades 3–4 thrombocytopenia in nine patients and grades 3–4 neutropenia in only three patients. In conclusion, treatment with bortezomib as single agent resulted safe and effective in a subset of heavily pretreated lymphoma patients with usually poor outcome. New future hypotheses of investigation are indicated. Copyright © 2012 John Wiley & Sons, Ltd.