Photodynamic therapy combines photosensitizers absorbing light in the red spectral region and irradiation with light of the corresponding wavelength. To analyse the influence of cell differentiation on susceptibility to photodynamic therapy, we compared the proliferation inhibition induced by photodynamic therapy on normal human keratinocytes, spontaneously transformed human keratinocyte cell line HaCat and on squamous cell carcinoma lines. Cells were irradiated with polychromatic methylene blue as well as the precursor of protoporphyrin, 5-aminolevulinic acid. When incubated with Photosan-3, normal human keratinocytes exhibited and ED50 about 10-fold lower than the other cell lines studied. When methylene blue and 5-aminolevulinic acid were used, photodynamic therapy had comparable effects on all cell types. Stimulation of normal human keratinocytes with either EGF-alpha or IFN-gamma resulted in an increase susceptibility to photodynamic therapy when 5-aminolevulinic acid was used. This effect was more pronounced in the case of EGF-alpha. Our experiments suggest that activation and differentiation are two important parameters determining susceptibility to photodynamic therapy.