OBJECTIVE: To examine the relationship between microaneurysm (MA) turnover using automated analysis of fundus photographs (RetmarkerDR; Critical Health SA) and development of clinically significant macular edema (CSME) in nonproliferative diabetic retinopathy (NPDR). RESEARCH DESIGN AND METHODS: A prospective, monocenter, observational study was designed to follow eyes/patients with type 2 diabetes and NPDR (Early Treatment Diabetic Retinopathy Study levels 20 and 35) with no prior laser treatment for 2 years or until development of CSME. A total of 410 patients, one eye per patient, fulfilled the inclusion/exclusion criteria and were included in the study. Ophthalmologic examinations including best corrected visual acuity, fundus photography, and optical coherence tomography were performed at baseline, 6 months, and at the last study visit (24 months or before laser treatment). RESULTS: A total of 348 eyes/patients performed the 24-month visit or developed CSME. Of these 348 eyes/patients, 26 developed CSME. HbA1c levels at baseline and MA turnover (i.e., the sum of the MA formation and disappearance rates) computed during the first 6 months of follow-up were found to be independently predictive factors for development of CSME. MA turnover was 11.2 ± 11.2 in the 26 eyes/patients that developed CSME and 5.0 ± 5.2 in the remaining 322 (P < 0.001). Higher MA turnover values correlated with earlier development of CSME. MA turnover predictive values for CSME development were, for the positive predictive value, 20% and for the negative predictive value, 96%. CONCLUSIONS: MA turnover calculated with the RetmarkerDR predicts development of CSME in eyes with NPDR. Low MA turnover values identify well the eyes that are less likely to develop CSME in a 2-year period.