We recently described a novel thiotepa plus etoposide high-dose therapy (HDT) conditioning regimen for aggressive histology non-Hodgkin's lymphoma (NHL) that had low regimen-related toxicity (RRT) and an efficacy rate comparable to other NHL HDT regimens. In this report, we describe the UW experience with the addition of total body irradiation (TBI) and pre-transplant involved-field radiation (IFRT) to the thiotepa + etoposide HDT regimen. Between 1992 and 1999, 28 patients with indolent or mantle cell lymphoma were treated on this protocol. With a median follow-up of 64 mo, the median event-free survival (EFS) was 24 months, and the median overall survival (OS) had not been reached. The median number of grade 3 - 4 non-hematologic toxicities was five. There were five deaths (18%) in the first three months after HDT due to RRT. In contrast, the thiotepa + etoposide conditioning regimen (without TBI or IFRT) given to 65 intermediate grade NHL patients resulted in only one treatment-related death and considerably fewer grade 3 - 4 toxicities. Given the relatively short EFS in this cohort of indolent NHL patients, we conclude that the combination of IFRT and TBI plus thiotepa and etoposide resulted in a HDT regimen with excessive toxicity and this protocol was closed at our institution.