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Abstract Background The purpose of this study was to outline the midterm follow-up results and complications in patients who underwent transthoracic device closure of an atrial septal defect (ASD) with the very large domestic occluder (44–48 mm). Methods The data of 35 patients who underwent transthoracic device closure of an ASD with the very large domestic occluder (44–48 mm) at our institution were collected prospectively between January 2010 and January 2015. All patients were invited for an outpatient visit and contrast TTE for 12–70 months after ASD closure. Results Thirty-four patients were occluded successfully under this approach and 1 patient was transferred for surgical repair for dislodgement of the occluder. The most frequent complication was transient cardiac arrhythmia. A new third degree atrioventricular block occurred in 1 patient who recovered 1 week later. During the follow-up period, we found no recurrence, no thrombosis, no device embolization, no device failure, and no cases of death. The total occlusion rate was 94.1% in the 12 months of follow-up, and the intracardiac structure and cardiac function were significant improved contemporaneously. Conclusion Transthoracic device closure of an atrial septal defect with the very large domestic occluder (44–48 mm) is a safe and feasible technique. However, long-term follow-up is required to better assess the safety and feasibility of this method for the closure of very large ASDs in patients.