AIM: To determine the risk factors of clinically significant macular edema (CSME) in patients with non-proliferative diabetic retinopathy (NPDR) in a multi-ethnics Malaysian population. METHODS: We performed a case control study in which 150 patients with bilateral NPDR and CSME in either eye were compared to 150 patients with bilateral NPDR and no CSME in both eyes. CSME and NPDR were graded according to Early Treatment of Diabetic Retinopathy Study criteria. Student’s t-test, odds ratio and multiple logistic regression analysis were performed to analyze the duration of diabetes, body mass index (BMI), blood pressure(BP), total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), fasting blood glucose (FBG), HbA1c, full blood count, serum creatinine and proteinuria between the two groups. RESULTS: Both groups were matched in terms of age, gender and ethnicity. Duration of diabetes, total serum cholesterol, serum LDL, FBG, HbA1c and serum creatinine were significantly higher in the CSME group (P<0.05). The hemoglobin, packed cell volume were significantly lower in the CSME group (p<0.05). There was no significant difference for serum HDL, TG, BMI, systolic and diastolic BP. Multiple logistic regression analysis showed that total serum cholesterol and HbA1c had significantly high odds of developing CSME. CONCLUSION: HbA1c and total cholesterol are the two most important risk factors associated with CSME in patients with NPDR.