The activation state of the members of the mitogen-activated protein kinase family following photodynamic therapy (PDT) with benzoporphyrin derivative monoacid ring A was investigated using a naturally transformed murine keratinocyte cell line, Pam 212. PDT involves the use of photosensitizer molecules and a specific wavelength of visible light. The process of PDT generates singlet oxygen and other reactive oxygen intermediates (ROIs), and the cytotoxic effect of these ROIs is the basis for the use of PDT to treat cancer and psoriasis. PDT caused a strong dose- and time-dependent activation of both stress-activated protein kinase (SAPK) and p38 HOG1. The maximum activation of SAPK and p38 HOG1 occurred between 20 and 30 min following PDT treatment with 200 ng/ml benzoporphyrin derivative monoacid ring A and 2 J/cm2 of red light at 690 nm. In our system, PDT did not cause significant activation of extracellularly regulated kinase (ERK) 1 and ERK2. Under the same experimental conditions, ultraviolet light irradiation caused strong activation of SAPK and p38 HOG1 and minimum activation of ERK1 and ERK2 in Pam212 cells. A number of ROI scavengers were tested for their effect on PDT-induced SAPK and p38 HOG1 activation. Both L-histidine and N-acetyl-L-cysteine showed a significant inhibitory effect on PDT-induced SAPK and p38 HOG1 activation. This indicated that PDT-induced SAPK and p38 HOG1 activation may be partially mediated by ROI.