Due to its radioresistance, the prognosis of glioblastoma multiforme (GBM) remains poor. Therefore, we investigated the impact of simultaneous radio-chemotherapy with topotecan (Hycamtin ®) on clinical outcome, tolerability and quality of life. In this multicenter trial, 60 patients (19 females, 41 males) with histologically proven (5× biopsy, 31× subtotal resection, 24× total resection) GBM were included. Radio-Chemotherapy was performed with daily doses of 2.0 Gy (total, 60 Gy), and 0.5 mg (absolute dose) of topotecan intravenously 1 h prior to irradiation. Toxicity was assessed using common toxicity criteria (CTC). General condition and quality of life were assessed at baseline, at the end of therapy, and 6 weeks post-therapy. Local control and length of survival were compared with an historical control group of 67 patients only treated with postoperative radiotherapy following stereotactic biopsy (15×), subtotal resection (39×), or total resection (13×). 57 patients completed the therapy. Median radiation dose was 60 Gy (range 16–76 Gy). Median cumulative topotecan dose was 15 mg (range 7.5–18.5 mg). CTC toxicity grade 3 was observed in six patients and grade 4 toxicity in two patients (three events). Two patients died of septic disease. Mean Karnofsky index was 87% at baseline, 81% at the end of therapy, and 80% at 6 weeks post-therapy. Median survival time was 15 months, significantly longer than the 11 months seen in the control group ( P < 0.002). Extent of tumour resection or patient age did not have a significant effect on survival. This multimodal approach is well tolerated, and quality of life remains preserved. The relatively long median survival time is promising but a further randomised double blind placebo controlled parallel designed clinical trial should be performed to confirm these results.