Since approximately 30% of leukemia patients relapse after allogeneic BMT using total body irradiation (TBI)-based preparative regimens, treatment intensity may be suboptimal. The killing of leukemia cells is proportional to the radiation absorbed dose. We studied the feasibility and toxicity of escalating the doses of fractionated TBI above our previous prescription of 13.5 Gy. Sixteen evaluable patients with advanced hematologic malignancies were treated with twice daily TBI using a high-energy source (18-24 MV). The first patient cohort (n = 11) received a total dose of 14.4 Gy in nine fractions, and the second cohort (n = 5) received doses escalated to 15.3 Gy. All patients received high-dose etoposide (60 mg/kg) and allogeneic stem cell transplantation following the TBI. All patients had HLA-identical sibling donors. The median times for neutrophil and platelet engraftment were 13.5 and 12 days, respectively, and did not differ between the two cohorts. All but one patient developed treatment-related grade 3 or 4 mucositis. There were three cases of grade 4 pulmonary toxicity and three cases of grade 4 hepatic toxicity among the 14.4 Gy cohort, and one case each of grade 4 pulmonary and hepatic toxicities among the 15.3 Gy cohort. In most cases comorbid conditions contributed to these toxicities. Two patients had significant GVHD of the GI tract. Six relapses occurred, five (45%) in the 14.4 Gy cohort and one (20%) in the 15.3 Gy cohort. The 100-day treatment-related mortality rates were 9% and 20% for the 14.4 Gy and 15.3 Gy cohorts, respectively, and the median survivals were 226 and 201 days, respectively. We conclude that TBI dose escalation above the previously used 13.5 Gy dose is feasible using a high-energy source and high-dose etoposide. Acute and chronic toxicities were primarily related to GVHD, infection and relapse rather than to TBI.