Erythema multiforme (EM) is a targetoid eruption with interface pathology often triggered by a hypersensitivity response to a variety of infections, most commonly herpes simplex virus. Hepatitis C virus is rarely associated with EM. We present a 37-year-old man with an 8-year history of severe EM unresponsive to valacyclovir, acitretin, and cyclosporin, and marginally responsive to high-dose prednisone. The eruption had cleared 6 years previously during treatment with interferon for his concurrent hepatitis C virus. Although his viral titer was undetectable, we initiated therapy with interferon and ribavirin. The patient responded dramatically within 2 months and remained clear of EM after 1 year of continued interferon therapy. This is the third case reported in the world literature documenting a response of EM to interferon, and the first case in which hepatitis C virus was undetectable in serum prior to interferon therapy.