The effects of topical PUVA treatment on the epidermal cyclic AMP system were investigated. 8-methoxypsoralen (8-MOP), 0.3% in ethanol was applied to the backs of pigs which were then irradiated with UVA. A significant increase in the epidermal beta-adrenergic adenylate cyclase response was observed 24 h after low (1.1 J/cm2) and moderate (2.1 J/cm2) dose irradiation. There was no significant change in the adenosine- or histamine-mediated adenylate cyclase responses. 8-MOP application or UVA irradiation alone had no effect on the beta-adrenergic adenylate cyclase response. PUVA treatment with a higher irradiation dose (4.2 J/cm2) produced no increase in the beta-adrenergic response and adenosine- and histamine-mediated adenylate cyclase responses were decreased. Cyclic AMP phosphodiesterase activity was decreased by PUVA treatments using UVA doses of 1.1 and 2.1 J/cm2; however, the change was not statistically significant. The increased beta-adrenergic response was also observed in the presence of the cyclic AMP phosphodiesterase inhibitor, isobutylmethylxanthine. These results indicate that epidermal adenylate cyclase responsiveness is affected by topical PUVA treatment in vivo.