The safety and efficacy of low-dose (10 mg) recombinant human tissue plasminogen activator (rhtPA: Activase: Genentech) was studied in 14 systemic sclerosis (SSc) patients. The patients were enrolled in a double blind, placebo-controlled crossover trial. Patients who met the inclusion criteria were enrolled in the study, given placebo or rhtPA, and then crossed over at 3 months. Assessment criteria included the Rodnan skin score; a daily patient diary to record side-effects, frequency, and severity of Raynaud's episodes and activity; and pulmonary function tests. Ten mg of rhtPA (Genentech) was administered over a 4 hour period using a myocardial infarction protocol. None of the patients experienced side-effects from the treatment protocol. No differences in the frequency or severity of Raynaud's episodes were noted during the two arms of the study. However, when the mean change of the Rodnan skin score in the placebo arm was compared to the rhtPA arm of the protocol, a significant difference was observed (0.8 vs. -5.4, p < 0.001). Three patients had moderate improvement and seven showed mild improvement. Mild deterioration or no change in study parameters was noted in 4 patients. This study has demonstrated that the administration of low-dose rhtPA is safe and is accompanied by modest improvement in symptoms of a subset of scleroderma patients.