BACKGROUND The clinical utility of transthoracic echocardiography with contrast (TTE-C) for detection of right-to-left shunt (RLS) remains unknown. In this meta-analysis we evaluated the accuracy of TTE-C for RLS diagnosis compared with transesophageal echocardiography (TEE) as the reference standard. METHODS A systematic review and meta-analysis was performed using a search of MEDLINE, EMBASE, PubMed, and Cochrane library databases. Studies that were included provided data to assess sensitivity and specificity of TTE-C compared with TEE for RLS detection. RESULTS A total of 35 studies, involving 4209 patients, were analyzed. The average patient age was 49.1 ± 11.2 years and 53.9% were male. For RLS detection in the entire cohort, TTE-C sensitivity was 73% (95% confidence interval [CI], 66%-80%) and specificity was 94% (95% CI, 92%-96%). The sensitivity of TTE-C was 80% (95% CI, 74%-86%) in studies published in 2000 or later compared with 51% (95% CI, 36%-65%) in those published before 2000. In studies that used harmonic imaging, TTE-C sensitivity was 82% (95% CI, 77%-87%) and specificity was 95% (95% CI, 93%-97%). Among those with patent foramen ovale closure indications, TTE-C sensitivity was 74% (95% CI, 59%-89%) and specificity was 98% (95% CI, 95%-100%). In patients in whom RLS was diagnosed using a guideline-suggested 3 cardiac cycle cutoff, TTE-C sensitivity was 75% (95% CI, 66%-83%) and specificity was 94% (95% CI, 92%-97%). Provocative manoeuvres increased sensitivity by approximately 40%. CONCLUSIONS TTE-C offers excellent specificity and moderate sensitivity for RLS diagnosis compared with TEE, and it might therefore serve as an initial screening modality for selected patients with a high likelihood of having RLS and for indications for treatment.