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Abstract Background Previous studies suggested that use of fenofibrate could significantly reduce the rate of progression into diabetic retinopathy (DR), and that retinal nerve fiber layer (RNFL) loss, which has been considered an important indicator for retinal neurodegeneration, might precede microvascular changes. The aim of this study was to assess the effect(s) of fenofibrate on RNFL thickness at early stage of DR in patients with type 2 diabetes mellitus (DM). Methods In this retrospective matched case-control study we included a cohort of 89 patients with type 2 DM, aged 40 or above, between Jan 1, 2017 and March 31, 2017. Among the subjects, 48 patients received fenofibrate therapy and the other 41 patients did not receive fenofibrate treatment. We defined use of fenofibrate as the presence of any prescription for fenofibrate within 1 year before or any time after the diagnosis of DM, and all the patients had either no DR or non-proliferative diabetic retinopathy (NPDR). The fibrate users were well matched with non-fenofibrate users for gender, age and axial length. The RNFL thickness in all quadrants of both eyes was examined with spectral domain optical coherence tomography (SD-OCT). The multiple linear regression analysis was used to assess the association of RNFL thickness with potential risk factors of DR other than fenofibrate use. Results The non-fenofibrate users had significantly reduced RNFL thickness of the superior quadrant of the right eye compared to the fenofibrate users (t = 2.384, P = 0.019). On the contrary, BMI (p = 0.034) and ACR (p = 0.024) were both negatively correlated to the RNFL thickness of the right eye. Conclusion Oral administration of fenofibrate was suggestively associated with thicker RNFL in superior quadrant of the right eye of patents with early DR.