Background: Intravenous immunoglobulin (IVIg) has recently been advocated as a treatment for pemphigus, but the results of published studies are in conflict. This study was conducted to re-examine the effectiveness of IVIg for the immediate control of active disease and to study the mechanisms of its action. Methods: Six patients with active pemphigus vulgaris unresponsive to conventional therapy with high doses of corticosteroids were treated with IVIg (400 mg/kg per day for 5 days) and concurrently given cyclophosphamide (100-150 mg/d). The primary end points were healing of skin lesions and changes in the level of intercellular antibodies and steroid dose. Results: New lesions ceased to form within 1 week of initiating IVIg therapy, and within 2 weeks the extent of existing skin lesions was reduced by 80% or more in all but one patient. Within 3 weeks, steroid doses were reduced by an average of 41%. The improvement was more rapid than that in patients previously treated with similar doses of steroids and cytotoxic agents at the same institution. Clinical improvement was associated with a rapid decline in pemphigus antibodies whose levels decreased by 72% within 1 week of initiation of IVIg therapy. The rapidity and extent of this decline were similar to those achieved with intensive plasmapheresis. The decline was not due to blocking the synthesis or the immunologic activity of intercellular antibodies by IVIg, suggesting that it resulted from increased immunoglobulin catabolism. Conclusions: These results indicate that IVIg can effectively and rapidly control active pemphigus unresponsive to conventional therapy and suggest that the mechanism of its action is decreasing serum levels of intercellular antibodies. (J Am Acad Dermatol 2002;47:358-63.)