Hematoporphyrin derivative (HPD) is a potent photosensitizer which localizes preferentially in malignant tumors. Parenteral administration of this compound followed by irradiation with the appropriate wavelengths of light has been used for the diagnosis and treatment of various epithelial neoplasms. In this study the effects of such treatment on immunological responses were evaluated by examining the capacity of HPD and light to inhibit contact hypersensitivity to dinitrofluorobenzene (DNFB) in C3H mice. Pretreatment of mice with HPD photoradiation resulted in 50% suppression of contact hypersensitivity to DNFB. Inhibition of the response could be produced even when sensitization with DNFB was attempted 2 weeks after a single irradiation procedure, indicating that HPD and light-induced inhibition of contact sensitivity was sustained phenomenon. Prior sensitization with DNFB followed by treatment with HPD and light elicited no immunosuppression. The immunosuppressive response required photoactivation of the porphyrin molecule, since mice treated with HPD alone or light alone developed little or no suppression. In adoptive transfer studies, it was shown that the immunosuppression was associated with the development of suppressor cells. These results indicate that photoradiation therapy with HPD and light can produce systemic suppression of contact hypersensitivity in mice. These data suggest that HPD photoradiation of malignant tumors may inhibit certain types of immune responses in humans.