Immortalized keratinocytes HaCaT is popular model for skin research (toxicity, irritation, allergic reactions or interaction of cells). They maintain stable keratinocyte phenotype and respond to keratinocyte differentiation stimuli. However, the programs of stratification and expression of differentiation markers in HaCaT keratinocytes are aberrant. HaCaT cells bear two mutant p53 alleles (R282Q and H179Y) which contain Gain-of-Function (GOV) mutations acquired as a result of spontaneous immortalization (mutp53). At the same time, mutp53 acts as a transcription factor, and also affects interaction of p63 protein with its transcription targets. It is known that proteins of the P53 family play an important role in regulating processes of proliferation and differentiation of human keratinocytes.At the same time, the role of mutp53 in these processes is not fully clear. We present data sets obtained as a result of high-performance proteomic analysis of immortalized HaCaT keratinocytes with p53 knockout in two different states: sub-confluent and confluent, which are characterized by different intensity of cell differentiation processes. As a protocol for proteomic profiling of cells, we used the approach of obtaining LC-MS/MS measurements followed by their processing with Progenesis LC-MS software (Nonlinear Dynamics Ltd.)