Scleromyxedema is a variant of papular mucinosis characterized by fibroblast proliferation and mucin deposition in the dermis. Historically, it has been very difficult to treat and can cause significant morbidity and mortality with systemic involvement. We describe a case of a woman with scleromyxedema and systemic manifestations treated with interferon alfa. Her skin responded very well to therapy within 3 months; however, her systemic manifestations showed little change. We conclude that interferon alfa may be a useful therapy for patients with scleromyxedema, particularly if the disease process is limited to the skin.