Many studies have shown that human skin in organ cultures containing pemphigus antibody undergoes acantholysis, the histologic hallmark of pemphigus vulgaris. This in vitro organ culture system provides a good model to determine if drugs used to treat pemphigus inhibit the effect of pemphigus antibody after it is produced. In this study we determined if hydrocortisone, dapsone, and 6-mercaptopurine (6-MP) could inhibit acantholysis observed in human skin organ cultures containing high constant levels of pemphigus plasma. In six experiments we demonstrated that hydrocortisone (10(-3) and 5 X 10(-4) M) present at the start of organ culture inhibited acantholysis induced by pemphigus sera. Thus, this study raises the possibility that the large doses of steroids used to treat acute pemphigus could act directly on the skin, inhibiting acantholysis in the presence of high titers of pemphigus antibody. Other effective immunosuppressive drugs, such as dapsone and 6-MP, probably do not act directly on the skin.