Treatment of an organism with UVB light or PUVA (8-methoxypsoralen + UVA light) not only leads to alterations in the irradiated skin but also to systemic immunomodulation, due to the release of several chemical mediators of immunosuppression like prostaglandins, acute-phase proteins, IL-1 inhibitor, alpha-melanocyte-stimulating hormone, propiomelanocorticotropin or other cytokines. A recently described mediator is urocanic acid, which is transformed by UV light in the skin from the trans- to the cis-isomer and that exerts a systemic immunomodulatory effect. In our experiments, treatment with PUVA or with cis-urocanic acid prevents the rejection of rat heart allografts in 50% and 40% of cases, respectively. Control grafts are rejected in fewer than 10 days. PUVA treatment of donor leukocytes before transfusion into the prospective recipient inhibits only their sensitizing, not their graft-protecting, effect on subsequent skin grafts in mice. PUVA treatment also prevents acute lethal GVH disease in mice after irradiation with a sublethal dose of x-rays and transfusion of semiallogeneic spleen cells. Treatment of recipient mice with cis-urocanic acid has the same effect. The humoral immune response to sheep erythrocytes is not influenced by cis-urocanic acid. These results demonstrate that PUVA treatment or its chemical mediator, cis-urocanic acid, may be used in transplantation and hematology as naturally occurring immunosuppressive agents, especially for the control and manipulation of GVH leukemia reaction.