The epithelial cell adhesion molecule (EpCAM) is a type I glycoprotein located on the surface of epithelial cells. It is strongly expressed in many neoplasms and already used in the diagnosis and distinction of various tumour subtypes. Comparative studies about EpCAM expression in cystic sellar lesions are lacking. Therefore, we analysed its distribution pattern in adamantinomatous (aCP) and papillary (pCP) craniopharyngiomas (CP) and Rathke's Cleft Cysts (RCC) using immunohistochemistry and gene expression profiling. Whereas the protein was not detectable in pCP (n = 10), all aCP (n = 64) showed distinct staining patterns. The vast majority of RCC (n = 10) also appeared positive, but these displayed notably lower labeling scores. Additionally, significantly higher mRNA levels were detectable in aCP (n = 19) when compared to pCP (n = 10) (p = 9.985(-8)). Furthermore, pediatric aCP cases, in general, exhibited stronger EpCAM staining levels compared to adult ones (p = 0.015). However, we were not able to verify this result on mRNA level. In summary, our findings demonstrate that EpCAM can be used as an additional distinction-marker for cystic lesions of the sellar region. Its unknown function in aCP and the presence of an approved monoclonal bispecific trifunctional antibody for cancer therapy are interesting starting points for further studies.