A prospective randomized controlled multicenter phase III trial was conducted to evaluate the effects of neoadjuvant chemotherapy with nimustine (ACNU)-cisplatin (CDDP) when used in conjunction with radiotherapy plus adjuvant temozolomide in patients with newly diagnosed glioblastoma. The study population was randomly assigned into one treatment and one control group. Both groups received radiotherapy followed by six cycles of adjuvant oral temozolomide (150-200 mg/m(2)) for 5 days every 28 days after surgery. Prior to radiotherapy, the treatment group also received two cycles, 6 weeks apart, of neoadjuvant chemotherapy with ACNU (40 mg/m(2)/day) and CDDP (40 mg/m(2)/day) infused continuously for 72 h. The primary end-point was median survival time. The study has closed after interim analysis with a total of 82 patients (48.8% of target number) due to unacceptable high frequency of toxicity profiles in spite of the promising actuarial survival outcome. Median survival time was 28.4 months [90% confidence interval (CI), 21.1 months to not available] in the treatment group and 18.9 months (90% CI, 17.1-27.4 months) in the control group (P = 0.2). The 2-year survival rate and progression-free survival time were 50.9% and 6.6 months (90% CI, 3.5-9.5 months) in the treatment group and 27.8% and 5.1 months (90% CI, 3.8-8.8 months) in the control group. Grade 3 or 4 toxicity was documented in 26 (68.4%) patients in the treatment group, including three neutropenic fever and one death from sepsis, while grade 3 or 4 toxicity occurred in 6 patients (15.8%) in the control group. The high frequency of serious hematological toxicity with ACNU-CDDP neoadjuvant chemotherapy followed by radiotherapy and adjuvant temozolomide limits its usage as primary treatment for glioblastoma. Future studies should aim to identify a subpopulation at reduced risk for ACNU-CDDP toxicity so that the potential of this protocol can be realized.