BACKGROUND: Paradoxical embolism through the patent foramen ovale (PFO) is a well-recognized mechanism for otherwise unexplained ischemic stroke. Although transthoracic contrast echocardiography (TCE) has been used frequently for noninvasive diagnosis of right to left shunt through PFO, its diagnostic accuracy appears limited, especially in patients with poor acoustic window. Since harmonic imaging (HI) can enhance the definition of contrast microbubbles, theoretical advantages of HI in the detection of right to left shunt through PFO using microbubbles can be considered. However, there are few data regarding the diagnostic efficacy of HI in the detection of right to left shunt through PFO. The purpose of this study was to compare the diagnostic value of transthoracic HI in the detection of right to left shunt through PFO in patients with stroke with that of fundamental imaging (FI). Methods: One hundred thirty-six consecutive patients with stroke (82 male, mean age:9) underwent TCE in both HI and FI and transesophageal echocardiography (TEE) during rest and Valsalva maneuver with intravenous administration of agitated saline. PFO was judged to be present if microbubbles appeared in the left atrium within 3 cardiac cycles of their appearance in the right atrium. TEE was regarded as the gold standard for assessing the diagnostic accuracy of TCE. Results: Right to left shunt through PFO was detected in 40 of 136 patients by TEE (29.4%). FI of TCE detected shunt through PFO in only 9 of 136 patients (6.6%). In contrast, HI detected shunt through PFO in 25 of 136 patients (18.4%). The overall sensitivity and specificity of FI and HI for detection of right to left shunt through PFO were 22.5%, 62.5% (p<0.05) and 100%, 100%, respectively. Valsalva maneuver during HI significantly increased the detection rate of shunt through PFO (during rest in 9 and during Valsalva maneuver in 25, p<0.05). CONCLUSION: HI with contrast microbubble injection significantly enhanced the detection of right to left shunt through PFO in patients with ischemic stroke compared with FI by transthoracic approach.