OBJECTIVES: Current guidelines still recommend transesophageal echocardiography (TEE) as reference method to diagnose interatrial shunts. The aim was to test the accuracy of high-end transthoracal echocardiography (TTE) to exclude inter-atrial shunts. METHODS: Prospective TTE and TEE study with second harmonic imaging to determine left-to-right shunt (L/R) by both colour Doppler or R/L by contrast echocardiography in patients with unexplained cerebrovascular incidents or newly detected valvular or myocardial disease. RESULTS: An inter-atrial shunt was diagnosed in 200 of 438 analyzed patients (117 males). Colour Doppler echocardiography visualized a shunt in 67 patients (34%) on TTE vs. 84 (42%) patients on TEE (p <0.0001). However injection of agitated blood with a valsalva maneuver detected 190 (95%) interatrial shunts by both TTE and TEE, but 10 shunts (5%) only by TTE. CONCLUSIONS: Our study shows that patent foramen ovale can safely be demonstrated with high-end transthoracic contrast- echocardiography. If additional studies confirm our results, TTE has the potential to become the method of choice in the diagnosis of PFO.