Trans-urocanic acid (trans-UCA) accumulates in the upper layers of the epidermis and can be isomerized to cis-UCA by UV light irradiation. Cis-urocanic acid possesses immunosuppressive properties that have led to its consideration as one of the initiators of UV-induced immunosuppression. High quantities of cis-UCA persist in human skin for prolonged periods in the summer months. In the present study, mice were injected intradermally with trans-UCA and cis-UCA three times a week for 4 weeks in order to ascertain the long-term effects of the presence of these compounds in the skin. The weight of mice and of their spleens were unaffected by the cis- or trans-UCA treatment. A decrease in thymus weight, accompanied by an increase in lymph node weight, was detected in the cis-UCA-treated mice compared with trans-UCA-treated mice and untreated controls. A net accumulation of lymphocytes and dendritic cells (DC) in lymph nodes was evident following cis-UCA treatment but the percentage of both CD4+ and CD8+ lymphocytes as well as Ia+ DC remained constant among the different treatment groups, indicating that there was no specific migration or proliferation of a particular subset of cells. The in vitro lymphoproliferative response of lymph node cells to the mitogen concanavalin A was significantly sup pressed by cis-UCA treatment. The density of Langerhans cells in the epidermis of the ears was not altered by the chronic cis-UCA treatment. However, chronic cis-UCA treatment did suppress the mixed skin lymphocyte reaction response utilizing epidermal cells from the ears (an uninjected area of skin), indicating a systemic suppression. Compared with trans-UCA treatment, chronic cis-UCA treatment did not cause a significant reduction in the contact hypersensitivity response to oxazolone or the delayed hypersensitivity response to herpes simplex virus. Thus, chronic treatment with cis-UCA led to the suppression of some, but not all, of the immune parameters that are affected by UVB irradiation.