A comparative, Non - randomized, Prospective, Cohort Study was conducted with the intention to identify the association of existence of Clinically Significant Macular Edema (CSME) with Thiazolidinedione (Glitazone) use among type-2 Diabetes Mellitus patients with Diabetic Retinopathy (DR); which was carried out for a period of 3 years at Retina Vitreous clinic of Aravind Eye Hospital, Madurai. A total of 100 subjects of Diabetic Mellitus with Diabetic Retinopathy are enrolled with Inclusion and exclusion criteria as per protocol. Among two arms; Group 1 (N=50) is Glitazone users & Group 2 (N=50) is Non-Users. Bilateral Retinal evaluation done for Diabetic retinopathy and Macular edema (ME) through slit lamp biomicroscopy for grading Clinically Significant Macular Edema and its prevalence. The overall Prevalence of CSME in the population is 37% in Glitazone users which states that the exposure group is at higher risk rate for getting CSME than did the Glitazone Non- User group Subjects. The Relative Risk Ratio (RR) by Fisher’s Exact Test done through 2*2 contingency table for the cohort data is 1.423. Statistically analyzed in Graph pad version 3 for the 2 X 2 contingency table for calculating Relative Risk ratio by Fisher’s Exact test in 2 sided method. The Relative Risk ratio is greater than 1 which signifies that the Glitazone exposure group had the higher risk of getting CSME when compared to Glitazone non users. Usage of Thiazolidinediones at the optimal doses will help in preventing hyperglycemia and also dose related adverse effect such as CSME. Therefore rational use of the Glitazones among Diabetic mellitus patients is advisable.