Cholesteatoma epithelium is characterized by a keratinocyte dysregulation with an aggressive growth that leads to the destruction of normal middle ear mucosa. The abnormal behavior of cholesteatoma epithelium seems to be induced by the presence of a heavy immune cell infiltrate releasing different cytokines and growth factors in high amounts. Middle ear mucosa rests are often observed within the cholesteatoma stroma or adjacent to the advancing front of cholesteatoma epithelium. This study investigated the presence of interleukin-1 (IL-1), transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), and epidermal growth factor-receptor (EGF-R) in the mucosa rests as well as the expression of an activation marker, 4F2. The findings were correlated with the features of a surrounding stroma with an enhanced immune cell infiltrate. Cholesteatoma epithelium showed a high staining intensity of IL-1, TGF-alpha, and EGF-R. In contrast to this, middle ear mucosa did not show any positive reactions for the mentioned factors. Epidermal growth factor immunoreactivity was found in neither cholesteatoma epithelium nor in middle ear mucosa residues. The authors found a high concentration of lymphocytes and macrophages in the surrounding stroma. Most of these cells expressed TGF-alpha, IL-1, and 4F2, suggesting an activated form. Results indicate that keratinocytes present in the middle ear mucosa do not appear to react to the stimuli released by the inflamed stroma, reflecting important differences in the cell biological features of the keratinocytes that form parts of both types of epithelium.