Background: PIP3, generated by PI3-K, activates Akt which inactivates AFX/FKHR, with the consequent decrease in p27/Kip.1 expression and enhancement of cyclin D1 expression through FRAP/mTOR. PTEN lipid phosphatase degrades PIP3 and negatively regulates Akt, whereas this is activated by EGFR through PI3. In glioblastomas, PTEN is mutated in 27%-40% and EGFR amplified in 60%-65% of cases. Materials and Methods: PTEN mutation and EGFR amplification by PCR, Akt, p27/Kip.1 and cyclin D1 by immunohistochemistry, apoptosis by TUNEL and MIB.1 LI were studied in a series of 65 operated glioblastomas. Results: EGFR amplification and PTEN mutation were present in 50% and 30% of glioblastomas, respectively. No relationship between EGFR amplification and PTEN mutation, and p27/Kip.1 and cyclin D1 was found. However, cyclin D1 was positive in 69% of Akt-expressing areas, whereas p27 was positive in 30% only. Conclusion: A direct relationship is more evident between cyclin D1 and p27/Kip.1 and Akt than with PTEN and EGFR.