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Background/objectives: To investigate the relative contribution of systemic risk factors to retinopathy in prediabetes using a nationally representative cohort in the US., Subjects/methods: A group of 2098 participants aged ≥40 years with available HbA1c and gradable retinal images from the National Health and Nutrition Examination Survey 2005-2008 were included in this retrospective cross-sectional analysis. Participants were stratified into control, prediabetes, and diabetes groups based on HbA1c and anti-hyperglycaemic medication use. Logistic regression was used to assess the contribution of potential systemic risk factors to retinopathy prevalence., Results: The prevalence of retinopathy in the prediabetes group was 7.69%. Multivariable logistic regression revealed an inverse association of female sex (OR, 0.25; 95% CI, 0.08-0.74; p = 0.02), eGFR (OR, 0.98; 95% CI, 0.96-1.00; p = 0.04), and fasting glucose levels (OR, 0.92; 95% CI 0.87-0.98; p = 0.02) with retinopathy in individuals with prediabetes and a positive association with a Race/Ethnicity classification of "Other" (OR, 6.05; 95% CI, 1.65-22.1; p = 0.01). Comparison of ORs between groups indicated differential associations of "Other" race, fasting glucose, and C-reactive protein (CRP) with retinopathy in prediabetes compared with diabetes., Conclusions: The prevalence of retinopathy among individuals with prediabetes in the NHANES database is similar to other studies. Our findings suggest that nonglycemic metabolic risk factors may be especially relevant to the risk of retinopathy in prediabetes and extend the previously suggested protective effect of female sex on retinopathy in diabetes to prediabetes. The increased odds of retinopathy in underrepresented racial/ethnic groups in the setting of prediabetes also have implications for risk assessment in this population., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)