Cardiac and extracardiac right-to-left shunts can be identified by transesophageal echocardiography (TEE) as well as by transcranial Doppler ultrasound (TCD) using contrast agents that do not pass the lungs. Currently, the appropriate performance of a Valsalva manoeuvre (VM) to provoke the shunt, the use of different contrast agents and the classification of the TCD results are still under debate. In this study, we looked also at possible side effects of provoked cardiac micro-emboli in the left and right hemisphere. Seventy-one patients were investigated by both TEE and bilateral TCD of the middle cerebral arteries. The following protocol was applied in a randomized way: (1) Echovist-300 without VM; (2) Echovist-300, VM for 5 seconds starting 5 seconds after the beginning of contrast injection; (3) repetitive short VMs in between 2 and 13 seconds after the beginning of Echovist-300 injection; and (4) repetitive short VMs in between 2 and 13 seconds after the beginning of agitated saline injection. Only if one of the tests (2-4) was negative, this particular negative test was repeated. Use of Echovist-300, but not of saline yielded 100% sensitivity in the detection of TEE-proven shunts. The repetitive VM was slightly superior to the conventional VM. Introduction of a threshold of two or even three microbubbles produced less falsely positive TCD results in comparison to the TEE. There was no difference in microbubbles. TCD using Echovist-300 is a sensitive method to identify TEE-proven cardiac right-to-left shunts. Repetitive VM is an alternative to conventional VM.