Background: The Action in Diabetes and Vascular Disease (ADVANCE) Study demonstrated that a fixed combination of perindopril and indapamide reduced the risk of major vascular events and mortality in patients with type 2 diabetes. This Echocardiographic Substudy was designed to determine the effects of this treatment on left ventricular diastolic function and left ventricular mass. Methods: Five hundred and fifty-five patients entering ADVANCE underwent quantitative echocardiography prior to randomization and after 6 months and 4 years of treatment with perindopril-indapamide or placebo. Main end points were left ventricular diastolic function (ratio of mitral E velocity/early medial mitral annular tissue Doppler velocity, E/Em, and left atrial volume index) and left ventricular mass index. Results: Overall, blood pressure was reduced in the perindopril-indapamide group compared with placebo. E/Em and left atrial volume index both increased over the 4 years. There was no effect of perindopril-indapamide on E/Em, although there was a small attenuation of the increase in left atrial volume index with active treatment. Left ventricular mass index was reduced by 2.7 g/m with active treatment (95% confidence interval -5.0 to -0.1, P = 0.04). Conclusion: Compared with placebo, the perindopril-indapamide combination reduced blood pressure and left ventricular mass in patients with diabetes, but did not improve left ventricular diastolic function. Left ventricular diastolic function worsened in both groups over 4 years, despite blood pressure reduction and reduction in left ventricular mass. Improving left ventricular diastolic function remains a challenge in patients with diabetes.