Although there is much written about the molecular definitions of "primary" glioblastomas (GBM), there is little known about the histological features of this predominant subtype. We hypothesized that the "small cell architecture" would represent a histological feature of most primary GBMs. This was tested by comparing the presence of the small cell phenotype with the presence or absence of amplification of the epidermal growth factor receptor (EGFR), a common event in primary GBMs. After a pilot study that found a correlation between this small cell phenotype and EGFR amplification, we selected 9 pure small cell GBMs (SCGBM) and 12 non-SCGBMs to be studied for EGFR amplification by fluorescence in situ hybridization (FISH). In this set of 21 cases, 8 of 9 SCGBMs and 5 of 12 non-SCGBMs were amplified for EGFR. We then correlated the EGFR status of 79 GBMs unselected for their histological features from a set that had been previously characterized in regard to EGFR amplification. Fourteen of 21 (67%) exclusively small cell neoplasms, 8 of 25 (32%) GBMs with both small cell and non-small cell areas, and 3 of 33 (9%) non-small cell GBMs were amplified for EGFR (p = 0.0004 with an exact test). We conclude that EGFR amplification is associated with a small cell phenotype in GBMs and that SCGBMs are an important component of "primary" GBMs.