Purpose : To determine the maximum tolerable total dose (MTD) of etanidazole (ETA) when administered with external beam radiotherapy (XRT) and as a continuous infusion during stereotactic brachytherapy for patients with malignant glioma (anaplastic astrocytoma or glioblastoma multiforme or mixed cell tumors). Methods and Materials : Seventy previously untreated patients were entered in a Phase I study. Prior to initiation of treatment, patients were stratified according to whether or not they were candidates for interstitial implantation. The implant patients (IMP, n = 17 pt) received accelerated fractionation XRT 20 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m 2 × 6 doses, a 2 week break and then interstitial implant to 50 Gy (4–7 days) with a continuous infusion of ETA over 90–96 h. The two sequentially conducted nonimplant arms started with accelerated fractionation XRT 2 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m 2 × 4–5 doses/week. NonIMP 1 arm ( n = 38) received a 2-week break before standard fractionated boost XRT of 20 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. NonIMP 2 arm ( n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Results : The dose-limiting toxicity (DLT) in the IMP group was the cramping/arthralgia syndrome (4) and the cumulative MTD was 26 gm/m 2. For both nonIMP 1 and 2 the DLTs were peripheral neuropathy and the cramping-arthralgia syndrome. The MTD for nonIMP 1 was 34 gm/m 2 and nonIMP 2, 30 gm/m 2. Conclusion : The clinical efficacy and radiation-related toxicity of these regimens are being evaluated. The doses of ETA that can be used with accelerated fractionation and with external beam irradiation plus brachytherapy have been established.