The CD40/CD40 ligand (CD40L) system has never been investigated in autoimmune bullous diseases belonging to the pemphigus group in humans. Skin biopsy specimens from 21 patients with pemphigus vulgaris, 10 with pemphigus foliaceous and healthy volunteers were studied by immunohistochemistry (for CD40 and CD40L) and reversal transcriptase polymerase-chain reaction (for CD40L), while sera were analyzed by enzyme-linked immunosorbent assay for soluble CD40L. In all pemphigus specimens, the basal and suprabasal layers of the epidermis and perivascular infiltrating cells were CD40+. CD40L+ cells moderately infiltrated the perivascular and interstitial dermis of pemphigus specimens. CD40L mRNA was strongly evident in all pemphigus samples while no signal was detected in the healthy controls. The expression of soluble CD40L was significantly greater in pemphigus sera than in controls. We showed here that the CD40/CD40L system is upregulated both in lesional skin and in serum of patients with pemphigus.