Objectives: In this study, we tried to determine the safety and outcomes of thrombolysis with tissue plasminogen activator of intravascular thrombus. Study design: Eighty consecutive children were treated between 1985 and 1999 in a tertiary care setting in a retrospective case series. There were 65 arterial thrombi (56 after cardiac catheterization) and 15 venous thrombi treated with tPA at an average dose of tPA of 0.5 mg/kg/hour for a median duration of 6 hours. Results: Clot resolution was complete in 65% of children, partial in 20%, and there was no effect in 15%. There were major complications in 40%, minor complications in 30%, and no complications in 30%. Two patients had cerebral ischemia secondary to hypotension because of profound bleeding, with intracranial hemorrhage in 2 additional patients. Clot resolution was not related to patient age or weight, dose, and duration of tPA therapy and fibrinogen levels. However, complications were more likely in patients who weighed less, had a longer duration of therapy, a greater decrease in fibrinogen levels, and who failed to have resolution of their clot. Conclusions: tPA therapy can be effective in the thrombolysis of intravascular thrombus in children, but is associated with a low margin of safety and an unknown risk–benefit ratio. (J Pediatr 2001;139:682–8)