Objective To explore the changes of plasma coupling factor 6 (CF6) in children with large atrial septal defect and different degrees of pulmonary hypertension. Methods A total of 160 patients with large atrial septal defect and different degrees of pulmonary hypertension from January 2010 to August 2012 were retrospectively analyzed. The age of the patients ranged from 4 to 16 (mean 9.7±2.1) months old, and the weight ranged from 3.5 to 8.3 (mean 6.9±2.1) kg. The participants were divided into three groups: atrial septal defect without pulmonary artery hypertension (control group, n=41); atrial septal defect with pulmonary artery hypertension, but not to a severe degree (A group, n=76); and atrial septal defect with severe pulmonary artery hypertension (B group, n=43). The plasma CF6 levels were determined and compared by radioimmunoassay between different groups; the relation of CF6 levels with degree of pulmonary artery hypertension was analyzed. Results The plasma CF6 level was (198.5±43.7) pg/mL in the control group, (167.7±89.8) pg/mL in A group, and (304.4±80.7) pg/mL in B group, showing no significant difference between control group and A group (P>0.05), but with that in B group being significantly higher than those of control group and A group (P<0.01). We also found that the ratio of systolic pulmonary artery pressure to systolic blood pressure was positively correlated with plasma level of CF6 in atrial septal defect children with severe pulmonary artery hypertension (r=0.781, P<0.01). Conclusion The plasma CF6 level is obviously increased in children with large atrial septal defect and severe pulmonary artery hypertension. CF6 may be one of the reasons for severe pulmonary artery hypertension.