The aim of the study was to determine the maximum tolerated dose (MTD) and safety of the combination of bortezomib and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) as first-line therapy in advanced, aggressive T-cell lymphoma. Patients received increasing doses of bortezomib on days 1 and 8 (weekly schedule, 1.0, 1.3, and 1.6 mg/m(2)/dose) in addition to 750 mg/m(2) cyclophosphamide, 50 mg/m(2) doxorubicin, 1.4 mg/m(2) vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5, every 3 weeks. Six cycles of therapy administered every 21 days were planned. Thirteen patients, who had stage III/IV chemonaive aggressive T-cell lymphoma, received a total of 55 cycles of treatment. One patient experienced hematologic dose-limiting toxicity (grade 4 neutropenia associated with febrile episode) at the 1.0 mg/m(2)/dose of bortezomib. There was no dose-limiting non-hematologic toxicity. The MTD was not reached at 1.6 mg/m(2) dose level of bortezomib. The overall complete remission rate in all patients was 61.5% (95% confidence interval = 31.6-86.1). Bortezomib can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced-stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II studies of bortezomib plus CHOP is 1.6 mg/m(2)/dose of bortezomib on days 1 and 8 every 3 weeks as first-line treatment.