Abstract: AIM To compare the efficacy of two contrast agents (CAs), namely, agitated saline (AS) and AS with blood (ASb), in the diagnosis of right-to-left shunt (RLS) by contrast-enhanced transcranial Doppler (c-TCD). METHODS The study was conducted in 521 consecutive patients with patent foramen ovale (PFO), who suffered from cryptogenic stroke and/or migraine. For each patient, we performed c-TCD both at rest and during Valsalva maneuver using two different contrast agents: AS and ASb and compared the results. RESULTS RLS was detected respectively in 30% at rest and in 45% during Valsalva maneuver using ASb, and in 14% and in 33% using AS (P<0.01). The positive rates of both ASb and AS during Valsalva maneuver were obviously higher than those at rest. The positive rate and the number of micro-embolic signals using ASb were statistically higher than those using AS. CONCLUSION SASb can significantly increase the efficacy of c-TCD contrast agent in the diagnosis of right-to-left shunt and clinically can be widely used as a standard contrast agent.