PURPOSE: To test the risk of progression to macular edema (ME) of different phenotypes of mild nonproliferative diabetic retinopathy (NPDR). METHODS: Data from 882 patients with mild NPDR, Early Treatment Diabetic Retinopathy Study grades 20 and 35, with no prior laser treatment, enrolled in four separate longitudinal studies during 2007-2015 using the same reading center and with the same inclusion criteria and were pooled for analysis. One eye per patient was followed for up to 2 years until development of ME. Ophthalmological examinations included best corrected visual acuity, color fundus photography (CFP), and optical coherence tomography (OCT). They were performed at baseline and 6 months, with the last visit at 12 or 24 months, depending on the study. The eyes/patients were classified as belonging to phenotypes A, B, and C on the basis of OCT central subfield thickness and microaneurysm activity. RESULTS: A total of 882 eyes/patients performed the 12- or 24-month visit or developed ME. Of these 882 eyes/patients that completed the studies, 103 developed ME, 14 from phenotype A (14 of 466: 3.0%), 48 from phenotype B (48 of 164: 18.6%), and 41 from phenotype C (41 of 252: 16.3%). Eyes/patients from phenotypes B and C showed much higher risks for ME development compared with phenotype A: odds ratio (OR) 95% confidence interval (CI): 13.30 (7.09-24.97) P < 0.001; OR (CI): 6.32 (3.36-11.90) P < 0.001, respectively. CONCLUSIONS: NPDR phenotypes based on microaneurysm turnover and central macular thickness OCT at the 6-month visit using CFP and OCT, both noninvasive examinations, identified the eyes at increased risk of developing ME.