Neoadjuvant chemotherapy (CT), prior to radical radiotherapy (RT), in the treatment of high-grade gliomas may offer several advantages over standard adjuvant CT. The addition of tamoxifen, which can circumvent P-glycoprotein (P-gp)-mediated chemo-resistance, also merits attention. We have evaluated the neoadjuvant regimen of cisplatin and etoposide after surgery of grade III–IV gliomas and prior to radical RT, with regard to response rates (RRs), overall survival (OS) and time to progression (TTP). The synergistic activity between etoposide and tamoxifen was also studied. Forty-four patients were included. CT regime: cisplatin 100 mg/m2 on day +1 and etoposide 100 mg/m2 on days +1 to +3 every 3 weeks for 3 cycles. The initial 24 were also treated with high-dose tamoxifen, 275 mg/m2 on days –3 to +3. An immunohistochemical analysis of P-gp, p53, vascular endothelial growth factor, Ki67 and bcl-2 was also performed. Median follow-up was 11.57 months. In the 16 patients with measurable disease after surgery, a RR of 12.5% was seen, with 37.5% of disease stabilizations and 31.25% of progressions. The median OS and TTP were 11.3 and 5.7 months. Excluding the three deaths possibly related to tamoxifen, grade 3–4 was low, mainly emesis. Favorable prognostic factors were age less than 60 years, extent of surgery, absence of measurable disease, and the absence of radiological necrosis and ring enhancement. Only high p53 expression was associated with better OS. We conclude that neoadjuvant cisplatin and etoposide is a feasible regime, although any real advantage over standard adjuvant CT is dubious. Short-course high-dose tamoxifen should not be used alongside primary CT.