Despite combinations of surgery, radiotherapy (RT) and chemotherapy used in the treatment of glioblastomas, mean and median survival rates in most patients remain 12 months or less after diagnosis. RT and nitrosourea after surgery are the standard combination for glioblastomas. They may induce acquired resistance and, consequently, non-operable glioblastomas is a unique biological and clinical situation allowing evaluation of intrinsic chemosensitivity. We assess the fotemustine (F) (100 mg/m2 day 1)/ cisplatin (CDDP) (33 mg/m2 days 1-3)/etoposide (VP16) (75 mg/m2 days 1-3) monthly regimen for efficacy in non-removable glioblastomas at presentation. Between 1995 and 1998, 33 consecutive patients with symptomatic non-removable histologically proven glioblastomas were treated: none of them had previously received chemotherapy, irradiation or surgical debulking. Objective response was evaluated by contrast enhancement with magnetic resonance imaging (MRI) scan after each treatment. Toxicity was moderate and mainly haematological (grade III-IV thrombopenia = 20/171 cycles; leucopenia = 25/171). Neutropenic fever was rare and no intracranial haemorrhages or treatment-related deaths were noted. Nausea and vomiting (grade 1), and asymptomatic hearing loss were common. Peripheral neuropathy occurred in 3 patients. Objective response rates were 9/33 (27%) (stabilisation = 17/33). Mean survival time was 14.4 (11.2 months in the 26 deceased patients) with a median survival of 10 months. Median survival rates at 6 and 12 months were 88% and 42%, respectively. 7/33 patients are still alive with median survival of 34.6 months. 7/33 (4/7 alive) were long-term survivors (range: 19-67 months). Neoadjuvant chemotherapy in non-resectable patients is safe allowing delayed RT. Phase II chemotherapy trials should include studies with a subgroup of non-resectable tumours.