Studies in experimental models have implicated histamine and prostanoids in ultra-violet B (UVB)- and cis-urocanic acid (UCA)-induced systemic immunosuppression. This study examined the hypothesis that UVB irradiation and cis-UCA suppressed contact hypersensitivity responses to hapten by induction of histamine, which in turn evoked a prostanoid-dependent component of immunosuppression. BALB/c mice were administered with a cis-UCA monoclonal antibody, a combination of histamine types 1 and 2 receptor antagonists, or indomethacin. Mice were sensitized to 2,4,6-trinitrochlorobenzene (TNCB) on their ventral surface 5 days after UVB irradiation, or cis-UCA or histamine administration. Ears were challenged with TNCB 5 days later. Cis-UCA antibody inhibited the suppressive effects of UVB by approximately 60% and confirmed that suppression of contact hypersensitivity responses by UVB was due, at least in part, to mechanisms involving cis-UCA. Histamine suppressed contact hypersensitivity responses and the effects of cis-UCA and histamine were not cumulative, suggesting that cis-UCA and histamine signal largely through the same pathway. The immunosuppressive effects of histamine were not affected by the cis-UCA antibody, consistent with the model that histamine acts downstream of cis-UCA. Administration of histamine receptor antagonists and indomethacin each approximately halved the UVB- and cis-UCA-induced systemic suppression of contact hypersensitivity responses. The effects of the reagents that inhibited the action of histamine and prevented prostanoid production were not cumulative, and suggested involvement in the same pathway. These results support the involvement of cis-UCA, histamine and prostanoids, in a sequence, in UVB-induced systemic suppression of contact hypersensitivity responses.