OBJECTIVE: To examine the relationship between subclinical diabetic macular edema (DME) and the development of clinically significant macular edema (CSME) in nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes. METHODS: A prospective, monocenter, observational study was designed to follow patients/eyes 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. Ophthalmologic examinations, including best-corrected visual acuity, fundus photography and optical coherence tomography (OCT), were performed at baseline, 6 months and a final visit. RESULTS: A total of 348 patients completed study follow-up; 26 eyes developed CSME. Six out of 32 eyes/patients presenting subclinical DME at baseline developed CSME (18.7%), while 20 out of 316 eyes without subclinical DME developed CSME (6.3%). Eyes/patients with subclinical DME presented a risk for DME progression 3.686 times higher than that of eyes/patients without subclinical DME (95% confidence interval 1.221-7.988). CONCLUSIONS: Subclinical DME in eyes with NPDR identified by center point thickness measured on a Stratus OCT is a good predictor of CSME development.