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IMPORTANCE: Diabetic retinopathy (DR) may progress from nonproliferative DR (NPDR) to vision-threatening DR (VTDR). Studies have investigated fenofibrate use as a protective measure with conflicting results, and fenofibrate is not typically considered by ophthalmologists in the management of DR currently. OBJECTIVE: To assess the association between fenofibrate use and the progression from NPDR to VTDR, proliferative DR (PDR), or diabetic macular edema (DME). DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used medical claims data from a large US insurer. Cohorts were created from all patients with NPDR 18 years or older who had laboratory values from January 1, 2002, to June 30, 2019. Exclusion criteria consisted of any previous diagnosis of PDR, DME, proliferative vitreoretinopathy, or treatment used in the care of VTDR. Patients were also excluded if they had a diagnosis of VTDR within 2 years of insurance plan entry, regardless of when NPDR was first noted in the plan. EXPOSURES: Fenofibrate use. MAIN OUTCOMES AND MEASURES: The main outcomes were a new diagnosis of VTDR (a composite outcome of either PDR or DME) or DME and PDR individually. A time-updating model for all covariates was used in multivariate Cox proportional hazard regression to determine hazards of progressing to an outcome. Additional covariates included NPDR severity scale, systemic illnesses, demographics, kidney function (based on estimated glomerular filtration rate level), hemoglobin A(1c), hemoglobin, and insulin use. RESULTS: A total of 5835 fenofibrate users with NPDR at baseline (mean [SD] age, 65.3 [10.4] years; 3564 [61.1%] male; 3024 [51.8%] White) and 144 417 fenofibrate nonusers (mean [SD] age, 65.7 [12.3] years; 73 587 [51.0%] male; 67 023 [46.4%] White) were included for analysis. Of these, 27 325 (18.2%) progressed to VTDR, 4086 (2.71%) progressed to PDR, and 22 750 (15.1%) progressed to DME. After controlling for all covariates, Cox model results showed fenofibrates to be associated with a decreased risk of VTDR (hazard ratio, 0.92 [95% CI, 0.87-0.98]; P = .01) and PDR (hazard ratio, 0.76 [95% CI, 0.64-0.90]; P = .001) but not DME (hazard ratio, 0.96 [95% CI, 0.90-1.03]; P = .27). CONCLUSIONS AND RELEVANCE: In this study, fenofibrate use was associated with a decreased risk of PDR and VTDR but not DME alone. These findings support the rationale for additional clinical trials to determine if these associations may be representative of a causal relationship between fenofibrate use and reduced risk of PDR or VTDR.