We prospectively examined whether surgical treatment of secundum atrial septal defects (ASDs) in patients > or =40 years old improves their long-term clinical outcome. Surgical treatment of secundum ASDs in adults > 40 years old is a subject of controversy because of the perception of good long-term clinical outcomes in patients with unrepaired ASDs and the lack of data from randomized trials. We recruited 521 patients > 40 years old with secundum ASDs referred for treatment; 48 were excluded. Patients were randomly assigned to surgical closure (n = 232) or medical treatment (n = 241). The primary and secondary end points were a composite of major cardiovascular events (death, pulmonary embolism, major arrhythmic event, embolic cerebrovascular event, recurrent pulmonary infection, functional class deterioration or heart failure) and overall mortality, respectively. We assessed possible prognostic markers. The analysis was performed on an intention-to-treat basis. The median follow-up period was 7.3 years (range 2 to 13). The risk of having the primary end point was significantly higher in the medical group, which had a univariate hazards ratio of 1.99 (95% confidence interval [CI] 1.23 to 3.22) and a multivariate hazards ratio of 1.85 (95% CI 1.08 to 3.17). Although the survival analysis did not reveal differences in overall mortality between the surgical and medical treatments (hazards ratio 1.71, 95% CI 0.76 to 3.86), the multivariate analysis, adjusted by age at entry, mean pulmonary artery pressure and cardiac index, demonstrated significant differences between the study groups (hazards ratio 4.09, 95% CI 1.41 to 11.89). Surgical closure was superior to medical treatment in improving both the composite of major cardiovascular events and overall mortality in patients > 40 years old with secundum ASDs. This superiority was related to the mean pulmonary artery pressure, age at diagnosis and cardiac index. Because of the higher risk of morbidity and mortality, we believe that anatomic closure should always be attempted as the initial treatment for ASDs in adults > 40 years old with pulmonary artery systolic pressure < 70 mm Hg and a pulmonary/systemic output ratio > or =1.7. The operation must be performed as soon as possible, even if the symptoms or the hemodynamic impact seems to be minimal.