- Objectives In a prospective study, we examined the effect of treatment with recombinant tissue plasminogen activator (r-TPA) on survival and morbidity in a series of high-risk children with infectious endocarditis (IE) after prolonged treatment with indwelling catheters. We hypothesized that r-TPA is an adjunctive therapy for dissolution of infected thrombi in drug-resistant IE. Study design In the prospective 3-year study (1998–2001), we identified high-risk children with chronic illness and prolonged treatment with indwelling catheters who developed IE and overwhelming sepsis. Patients were allocated to receive r-TPA after persistent and enlarging intracardiac vegetations and failure to respond to conventional medical management. Complications associated with treatment, survival, and cardiac morbidity were observed. Results Seven infants were treated prospectively with r-TPA. All infants responded promptly to treatment, with resolution of the intracardiac vegetations within 3 to 4 days of commencement and without any adverse complications. All patients survived without long-term cardiac morbidity. Conclusion Recombinant tissue plasminogen activator may offer a safe alternative to surgical intervention in the high-risk infant with IE.