The host–parasite interaction between the rainbow trout Oncorhynchus mykiss and the fish louse Argulus japonicus was investigated by administering low levels of dietary cortisol before infecting the fish with low numbers of the parasite. After 24 h, the dietary cortisol treatment elevated blood cortisol and glucose levels and stimulated the synthesis of secretory granules in the upper layer of skin cells. Infection with 6 lice per fish caused skin infiltration by lymphocytes, also in areas without parasites. The lymphocyte numbers in the blood at 48 h post-parasite infection were reduced. Other changes, typical for exposure to many stressors and mediated by cortisol, were also found in the epidermis of parasitized fish, although neither plasma cortisol nor glucose levels were noticeably affected. Glucocorticoid receptors were localized immunohistochemically and found in the upper epidermal layer of pavement and filament cells, and in the leucocytes migrating in these layers. Cortisol-fed fish had reduced numbers of parasites and the changes in the host skin are likely involved in this reduction. Thus a mild cortisol stress response might be adaptive in rejecting these parasites. Further, the data suggest that this effect of cortisol is mediated by the glucocorticoid receptor in the skin epidermis, as these are located directly at the site of parasite attachment and feeding in the upper skin cells that produce more secretory granules in response to cortisol feeding.