Epidermal growth factor receptor (EGFR) is commonly overexpressed in adult high-grade gliomas. Forty to 50% of such tumors demonstrate amplification of the EGFR gene, often with rearrangement and constitutive activation of the gene product, suggesting that EGFR might play a role in the malignant progression of a subset of these neoplasms. In this regard, several groups have shown that overexpression of EGFR is associated with an adverse outcome in adult gliomas. In contrast to the extensive studies of EGFR status that have been performed in adult high-grade gliomas, little information has been reported about EGFR expression and amplification, as well as their prognostic relevance in high-grade gliomas of childhood, which carry a somewhat more favorable prognosis than their adult counterparts. To address this issue, we examined the expression of EGFR using immunohistochemistry and screened for amplification of the EGFR gene using a competitive PCR in a series of 27 archival pediatric high-grade nonbrainstem gliomas treated consecutively at our institution between 1975 and 1992. Tumors were categorized based on protein expression patterns, and the association between expression status and outcome was examined. Although elevated immunoreactivity for EGFR was observed in 80% of tumors, only two of the cases had gene amplification. No difference in outcome was observed between tumors that exhibited extensive EGFR immunoreactivity and those that did not (P > 0.3). Although EGFR expression did not seem to be of prognostic relevance for the outcome of pediatric patients harboring high-grade nonbrainstem gliomas, the consistently high levels of expression of EGFR in these neoplasms suggest that this receptor plays a role in the malignant phenotype of these tumors. Accordingly, treatment approaches targeting EGFR might be of potential therapeutic benefit for high-grade gliomas of childhood.