Brain stem tumors are among the most resistant brain tumors to therapy. The majority progress within 18 months of diagnosis and treatment. Multiple-fraction-per-day (MFD) radiotherapy would theoretically allow higher total doses of radiotherapy to be delivered in order to improve local tumor control without increasing neurotoxicity secondary to treatment. Seventeen patients with brain stem tumors were evaluated and treated at Duke University Medical Center (DUMC) from 1985 to 1991 with a MFD regimen. Six patients were accrued to Pediatric Oncology Group (POG) Protocol 8495 and were not included in this analysis, leaving eleven patients for review. Local fields were treated with fraction sizes of 110 or 117 cGy twice daily. There were 3 patients who received a total of 60.5-68.2 Gy and 8 who received 70.2-71.5 Gy. Initial and follow-up CT and/or MRI studies were available for review on all but one patient. All patients had progression of disease and have died. Median time to tumor progression was 5.8 months. Median overall survival was 11.2 months. There was no significant influence upon time to tumor progression or survival by total radiation dose received. Patients were classified by imaging group per the criteria of Stroink et al. based on review of their pre-treatment CT or MRI scans. One patient had no initial films available, 2 were in Group II (no contrast was given to separate A or B), 3 in IIA, 4 in IIB, and 1 in III. Autopsy in 3 patients failed to demonstrate histologic evidence of injury attributable to radiotherapy. The results of this study fail to demonstrate a positive impact of MFD radiotherapy on the outcome of children with unresectable brain stem tumors. © 1993 Kluwer Academic Publishers.