Despite their benign histological appearance, juvenile angiofibromas sometimes exhibit an aggressive growth behavior. Molecular and genetic analyses have detected beta-catenin mutations and androgen receptor gene gains in this tumor. Because intensive cross-talk among beta-catenin, androgen receptor, and C-MYC has been detected recently, we analyzed expression of the C-MYC protooncogene (MYC) on the genetic, transcriptional and translational level in seven sporadic juvenile angiofibromas. Two-color in situ hybridization analyses for chromosome 8 and MYC found in all seven juvenile angiofibromas significant MYC losses. In the three advanced juvenile angiofibromas of this series (Fisch stages III and IV) additional significant MYC gains were observed demonstrating a genetic heterogeneity for the MYC protooncogene. In cases of genetic MYC heterogeneity, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, Western blot investigations, and immunohistology showed increased C-MYC mRNA and protein levels. Semiquantitative RT-PCR analyses from laser microdissected endothelial cells and fibroblasts found no differences of C-MYC mRNA levels, leaving open the question of the neoplastic cell in juvenile angiofibromas. The finding of genetic MYC heterogeneity associated with C-MYC overexpression on the mRNA and protein level in advanced juvenile angiofibromas indicates involvement of the MYC oncogene in aggressive growth behavior.