Previously we demonstrated median survival of 69 weeks after combination therapy of permanent, low-activity I-125 seeds and BCNU wafers for recurrent glioblastoma multiforme (GBM). We designed this prospective phase I trial to assess efficacy of this combination treatment for newly diagnosed GBM. Patients with newly diagnosed GBMs deemed amenable to gross total resection were included. This dose-escalation study of I-125 seeds included three 6-patient cohorts, receiving increasing doses of 3000, 6000, and 9000 cGy, and a maximal number of BCNU wafers placed surgically. Postoperatively patients underwent standard fractionated radiation to 5,940 cGy followed by temozolomide chemotherapy. During enrollment of the first 6-patient cohort, the trial was stopped when 3 of 5 patients developed radiation toxicity. Five patients (median age 55 years, range 46-64 years) completed postoperative radiation; Karnofsky Performance Status ranged from 70 to 90. This lowest-dose cohort received I-125 seeds at 3,000 cGy and maximal BCNU wafer placement, and reached endpoint (median 26 weeks follow-up). Two patients developed local disease progression (median 34.4 weeks). The 3 patients who developed radiation toxicity, which was documented on follow-up MRI and confirmed by MRI spectroscopy (median 20 weeks), underwent treatment with steroids and bevacizumab. Our phase I study was closed during enrollment of the first 6-patient cohort because of the high incidence (60 %) of early radiation toxicity. We do not recommend the seed-wafer therapy for newly diagnosed GBM patients but rather reserve this as salvage therapy for select patients with recurrent GBM.