Gliomas account for 40% of primary central nervous system tumors in western countries, and about one third (37.3%) in Egypt. Identification of the cellular origin of gliomas, presents an opportunity for improving treatment strategies. It has been postulated that astrocytomas (represent 75% of gliomas) may be originated from cancer stem cells. Hypoxia may be a critical component of a stem cell niche and contributes to the tumor initiation and maintenance of cancer stem cells. In the present study, we hypothesized that the expression of stem cell marker (nestin) and hypoxia marker (Hypoxia-inducible factor-1α, HIF-1α) may be upregulated in astrocytomas. To explore our hypothesis, this work has been conducted to analyze the immunohistochemical profile of nestin and HIF- 1α in astrocytomas and to correlate their expression in different grades of the tumor. Material and methods: Paraffin-embedded sections of forty three specimens of astrocytic tumors (9 pilocytic astrocytoma, 13 diffuse astrocytomas, 7 anaplastic astrocytomas, and 14 glioblastoma multiforme) and 6 normal brain tissue (as a control) were stained with nestin and HIF-1α using standard immunohistochemical approaches. The immunoreactivity for nestin and HIF -1 α in both tumor cells and vascular endothelial cells were evaluated. Correlation between nestin and HIF-1 α expression was also studied. Results: The expression of nestin in tumor cells was present in 88.4% of cases. As compared to normal brain tissue, there was statistically significant (P < 0.01) gradual increase in the mean of nestin immunoreactivity score (IRS) with increasing grade of the studied astrocytomas (I –IV) (0.0+0.0, 1.7+1.8, 2.5+1.6, 5.7+3.2, and 7.8+2.5, respectively). The expression of hypoxia-inducible factor -1 α was seen in 65.1% of studied cases. The IRS of HIF -1 α showed significant (p >0.001) difference between low grade astrocytomas (pilocytic astrocytoma and diffuse astrocytomas) and high grade astrocytomas (anaplastic astrocytomas and glioblastoma multiforme). There was statistically significant positive correlation between expression of nestin and HIF-1α in both tumor cells and vascular endothelial cells (r =0.71, r=0.47 respectively and P< 0.001 for both). In conclusion: Intense expression of nestin in high grade astrocytomas may be helpful in their diagnosis especially in small biopsy. Determining the crosstalk between hypoxia and cancer stem cells will enhance the understanding of tumorigenesis and may provide new therapeutic strategy.