Background: Pruritus of unknown origin is a common complaint, and systemic causes must be considered. However, there is little data on how frequently systemic causes are responsible or whether any patient characteristics make a systemic cause more likely. Objective: We attempted to determine how frequently pruritus of unknown origin had a systemic etiology in an outpatient population seen in a university dermatology department and whether any patient characteristics made a systemic explanation more likely. Methods: This is a retrospective study using chart reviews and telephone interviews to collect data. Results: Of 50 patients, 11 had a systemic cause of pruritus. Pruritus was the initial symptom of systemic disease in 7 of these patients. No patient characteristics were statistically associated with systemic causes of pruritus. Conclusion: Pruritus of unknown origin was the initial symptom of a systemic disease in 7 of 50 patients presenting to a dermatology clinic with this complaint. The underlying diseases included hypothyroidism, gastric adenocarcinoma, hepatitis C, HIV, laryngeal carcinoma, graft-versus-host disease, and chronic lymphocytic leukemia. (J Am Acad Dermatol 2001;45:892-6.)