The effects of sodium dodecyl sulfate (25 mg/ml) and Triton X-100 (12.5 mg/ml and 25 mg/ml) on the HaCaT immortalized keratinocytes exposed to these surfactants for 48 h were studied. Using shotgun proteomics, a comparative analysis of the proteomic profiles of control and experimental cells after surfactants exposure was carried out. 260 common proteins were identified in control and experimental cells; 33 proteins were found in cells exposed to all three treatments, but not in control cells. These 33 proteins apparently reflect a nonspecific (universal) response of cells to toxic damage by the surfactants. These proteins are associated with activation of cell proliferation, changes in the functional activity of their ER and mitochondria, increased mRNA stability and activation of protein degradation processes in the cells. The possibility of using these proteins as a nonspecific parameter of cell response to cytotoxic damage is discussed. The mass spectrometry proteomics data (“raw”, “mgf” and “xml” files) have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers PXD007789 and PXD007776.