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This article describes a neonate with protein S deficiency who presented with life-threatening thrombosis of the aorta. This is the first case report of a neonate with protein S deficiency presenting with aortic thrombosis.A 9-day-old boy presented with a history of dark colored urine, vomiting, and apnea. The clinical examination was consistent with a coarctation of the aorta. An echocardiogram showed a normal arch of the aorta. An abdominal ultrasound done revealed an incompletely occluding thrombus in the aorta starting between the celiac axis and superior mesenteric artery to the aortic bifurcation. The patient was started on recombinant tissue plasminogen activator along with heparin and fresh frozen plasma.With tissue plasminogen activator, we were able to reestablish flow across the obstruction within a week. The patient had hypertension and renal failure that still requires dialysis.Protein S deficiency should be considered in a neonate with aortic thrombosis, and it can be treated successfully with a combination of high-dose tissue plasminogen activator and heparin followed by long-term heparin use.