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Introduction Non-catheter-related aortic thrombosis is a rare condition in neonates. It may be life threatening or leads to severe complications. It occurrence requires looking for an underlying congenital prothrombotic condition. Methods We report a case of a spontaneous aortic thrombosis in a newborn revealing an association of factor V Leiden and hyperhomocysteinemia. Results A full term male was born by c-section. He presented immediate severe respiratory distress. Echocardiography performed at the second day of life, showed persistent pulmonary hypertension. He required high frequency oscillatory ventilation and inhaled monoxide administration. Initial respiratory stabilization was noted. But at 11 days age, we noted an increase in oxygen requirement; a tachycardia, a hepatomegaly, an edema and femoral pulses were no more detected. Control echocardiography showed a left ventricular dysfunction with an ejection fraction of 30%. The abdominal doppler ultrasound found an extensive thrombosis in infrarenal abdominal aorta. Thrombolytic treatment was not administrated as a subarachnoid hemorrhage was found in the cerebral ultrasound. After 48 hours of mechanical ventilation and inotropic support, hemodynamic and respiratory stabilization was obtained. Control echocardiography at day 14, showed an ejection fraction of 50%. The biological assessment revealed heterozygosis R506Q mutation for the factor V (factor V Leiden) and heterozygosis MTHFR C677T mutation (hyperhomocysteinemia). The aortic thrombosis has been spontaneously lysed and disappeared within 10 months. At 4 years, his physical examination is normal. Conclusions Till now, there are no clear establisched guidelines concerning the management of arterial thrombosis. We insist that the blood clotting screen must be systematic and complete to look for association of congenital prothrombotic conditions which would increase the thrombotic risk.