Thirty-four adults with malignant lymphoma at high-risk for relapse were treated on a Phase I-II study of high-dose thiotepa (THIO), busulfan (BU) and cyclophosphamide (CYC) with autologous marrow or peripheral blood stem cell support. Four patients were in untreated relapse, 7 had stable or progressive disease, 12 were in partial remission, and 11 were in complete remission after reinduction chemotherapy before proceeding to the preparative regimen. Median follow-up time is 22 months. Grades 3-4 regimen-related toxicity occurred in 3 (14%) of 22 patients treated with THIO 250 mg/m2 x 3, BU 1 mg/kg x 10 and CYC 50 mg/kg x 3, and this was considered the maximal tolerated dose-schedule. Of the 23 patients with active disease at the time of transplantation, 52% (95% CI 31-73%) achieved a complete response, and 26% (95% CI 10-48%) achieved a partial response. For all patients, median time to progression was 13 months, median survival was 16 months, and disease-free survival at 18 months was 34% (95% CI 18-51%). The combination of THIO, BU and CYC is tolerable as a preparative regimen for lymphoma and has a high response rate, but further measures are needed to reduce the relapse rate for patients with advanced disease.