Objective To assess the effectiveness of a novel ultrasound wire for echo-guiding percutaneous atrial septal defect (ASD) closure in a sheep model. Methods After right lateral thoracotomy, ASDs were created in 20 sheep by transseptal needle puncture followed by balloon dilatation. Animals were evenly randomized into 2 groups to undergo ASD closure using echography as the only imaging tool with either COOK wire (control group) or new ultrasound wire (study group). The total procedural time, passing time (time needed for the guide wire to enter the left atrium), frequency of delivery sheath dropping into the right atrium, frequency of arrhythmias, and 1-week rate of complications were compared between the two groups. Results All animals survived defect creation procedures uneventfully. ASD devices were successfully implanted in all sheep. Compared with the control group, the study group had significantly (P < 0.05) lower mean procedure time (15.36 ± 4.86 versus 25.82 ± 7.85 min), lower mean passing time (2.69 ± 0.82 versus 5.58 ± 3.34 min), lower frequency of the guide wire dropping into the right atrium (0% versus 40%), and lower frequency of atrial (4.41 ± 2.61 versus 9.60 ± 3.68) or ventricular premature contractions (0.75 ± 0.36 versus 1.34 ± 0.68), respectively, without serious complications up to one week. Conclusion The novel ultrasound specialized guide wire was effective in echo-guiding percutaneous ASD closure.