Pemphigus vulgaris is a cutaneous autoimmune disease in which the occurrence of autoantibodies directed against desmoglein-3 and other self-antigens has been well established in patient sera. However, V-region interactions (connectivity) of serum IgG and IgM have not been analysed to date. In this report, it has been demonstrated that IgG and IgM in the sera of pemphigus vulgaris patients bind a preparation of F(ab′)2 fragments fractionated according to their isoelectric points, and that a pattern of connectivity distinguishable from that of healthy donor sera arises when the sera are tested against 20 individual isoelectric-focusing-separated F(ab′)2-containing fractions. This suggests that there are alterations in regulatory networks. In spite of the fact that prednisolone-based treatment of pemphigus patients has proved to be effective in controlling the disease, some undesirable effects associated with this form of treatment have prompted investigation into other therapeutic approaches. One possible approach to the treatment of this autoimmune disease is the use of high doses of normal polyclonal immunoglobulins. In fact there are a few reports of the empirical intravenous administration of immunoglobulins to pemphigus vulgaris patients. The results presented here provide the rational basis for using such a treatment, since it is demonstrated that a deviation from healthy V-region interactions can be attributed to pemphigus patients and that such a condition is considered to be modified by this type of immunotherapy.