The surgical closure of an atrial septal defect is frequently recommended for patients over 40 years of age. However, the prognosis for such patients with unrepaired defects is largely unknown, and the outcome for patients operated on after the fourth decade of life has not yet been compared with that for medically treated patients in a controlled follow-up study. In a retrospective study, we examined the clinical course of 179 consecutive patients with isolated atrial septal defects diagnosed after the age of 40. The 84 patients (47 percent) who underwent surgical repair were compared with the 95 patients (53 percent) who were treated medically. The mean (+/-SD) follow-up period was 8.9 +/- 5.2 years (range, 1 to 26). Multivariate analysis revealed that surgical closure of the defect significantly reduced mortality from all causes (relative risk, 0.31; 95 percent confidence interval, 0.11 to 0.85). The adjusted 10-year survival rate of surgically treated patients was 95 percent, as compared with 84 percent for the medically treated patients. In addition, surgical treatment prevented functional deterioration, as measured by the New York Heart Association class (relative risk, 0.21; 95 percent confidence interval, 0.08 to 0.55). However, the incidence of new atrial arrhythmias or of cerebrovascular insults in the two groups was not significantly different. The surgical repair of an atrial septal defect in patients over 40 years of age, as compared with medical therapy, increases long-term survival and limits the deterioration of function due to heart failure. However, surgically treated patients should be followed closely for the onset of atrial arrhythmias so as to reduce the risk of thromboembolic complications.