Background: Patients with pemphigus vulgaris (PV) are genetically linked to two alleles of the HLA subgroup, and circulating antibodies were found in first-degree relatives of these patients, thus showing genetic predisposition. Objective: Our purpose was to determine the occurrence of circulating true PV-IgG in patients' relatives. Methods: Circulating PV-IgG was determined in 21 first-degree relatives of 12 patients with PV by indirect immunofluorescence on monkey esophagus, carcinoma A431 cultures, and Western immunoblotting. Direct immunofluorescence was performed on skin biopsy specimens of 20 relatives. Results: Circulating PV-IgG was detected in 15 relatives (71%) by all methods tested. Good correlation was found between immunoblot reactivity and immunofluorescence. Of the 15 'positive' relatives, only five showed fixation of IgG to epidermal cells in vivo. Conclusion: The permeability of the epidermis or epidermal cell reactivity in vivo probably controls the expression of disease in patients' relatives.