The receptor for epidermal growth factor (EGF) plays an important role in epidermal keratinocytes and is known to move out of lipid raft after cholesterol depletion, leading to ligand‐independent activation. Accumulation of evidence indicates the ability of EGF receptor (EGFR) to undergo internalization without participation of the ligand under the control of p38 MAPK during stress conditions. Since cholesterol depletion using methyl‐beta‐cyclodextrin is known to induce ligand‐independent activation of EGFR in keratinocytes, we investigated by confocal microscopy and ligand‐binding tests the processing and localization of EGFR following lipid raft disruption. Here, we report the dimerization and the slow internalization of the receptor accompanied by the delayed phosphorylation of tyrosine 1068 and its degradation by the proteasome. We also demonstrate the involvement of p38 MAPK during the process of internalization, which can be considered as a protective response to stress. Moreover, cholesterol‐depleted keratinocytes recover their ability to proliferate during the recovery period that follows lipid raft disruption. J. Cell. Physiol. 217: 834–845, 2008. © 2008 Wiley‐Liss, Inc.