PURPOSE: To examine the relationship between microaneurysm turnover (formation rate), using a new semi-automatic method (MA-Tracker) based on color fundus photographs, and diabetic retinopathy (DR) progression to clinically significant macular edema (CSME). METHODS: In total, 113 patients/eyes with nonproliferative DR (NPDR) were followed up every 6 months for 2 years as controls of the DR clinical trials, and by conventional general and ophthalmological care for the next 8 years (over a total of 10 years' follow-up). Microaneurysm turnover for the 2 first years was computed using the MA-Tracker. RESULTS: The 17 patients that developed CSME over the 10 years of follow-up presented a microaneurysm formation rate of 9.2 +/- 18.2 microaneurysms/year (mean +/- SD) during the first 2 years, which was statistically higher than the eyes that did not develop CSME (0.5 +/- 1.2 microaneurysms/year, p < 0.001). These 17 patients also presented higher HbA(1C) levels at baseline (8.5 +/- 1.2%) compared to the patients who did not develop CSME (7.3 +/- 1.2%, p = 0.001). CONCLUSIONS: A high microaneurysm formation rate on color fundus photographs appears to be a good biomarker for DR progression to CSME in type 2 diabetic patients with NPDR.