Severe thrombosis of a mechanical valve is a rare complication in pediatric patients. Thrombolytic therapy as treatment of mechanical mitral valve thrombosis has rarely been reported in young infants. We report the successful treatment with recombinant tissue-type plasminogen activator of a mechanical mitral valve thrombus in a 7 month-old patient with trisomy 21, complete atrioventricular canal defect and pulmonary hypertension status post complete atrioventricular canal repair and subsequent prosthetic mitral valve replacement. He presented with respiratory decompensation and shock secondary to severe mechanical mitral valve stenosis. Serial echocardiograms showed significant resolution of the thrombus within 18 h of infusion with no major bleeding complications during the treatment course. Although a rare complication of mechanical valve placement in pediatrics, thrombosis of mechanical valves may result in severe hemodynamic and respiratory compromise. This case demonstrates that thrombolytic therapy is a feasible option for the treatment of critical thrombosis in pediatric patients after MVR.