The metabolism of methysergide was studied in five healthy adult subjects and three patients who had previously developed retroperitoneal fibrosis while receiving long-term therapy with 14C-methysergide maleate. All patients were asymptomatic and had normal renal function at the time of study. Subjects and patients did not differ in regard to serum radioactivity data or urinary excretion of total radioactivity and methysergide radioactivity. They also excreted radioactive carbon dioxide (14CO2) into the expired air at similar rates, suggesting that both groups were able to demethylate methysergide to form methergine. These three patients thus appear to metabolize a single test dose of methysergide in a normal manner; the pathogenesis of retroperitoneal fibrosis in such patients remains unknown.