Thirteen patients with systemic sclerosis were treated with isotretinoin. Nine patients completed between 6 and 14 months of treatment and all showed an improvement in the cutaneous manifestations of their disease. The drug did not appear to benefit internal organs affected by the disease. Most patients experienced the well-recognized side-effects of retinoids, which in three cases necessitated withdrawal from the study within 3 months. Serum levels of type III procollagen aminopropeptide did not show a consistent decline during treatment, despite a clinical improvement. The mode of action of the reported therapeutic effect of isotretinoin in systemic sclerosis is unclear. There may be a preferential suppression of the synthesis of type I collagen, or the drug may be acting by an unrelated mechanism.