AIM: To assess and compare the utility of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and red blood cell distribution width (RDW) as potential biomarkers to predict the severity of diabetic retinopathy (DR) in the United States population. METHODS: The observational study enlisted patients diagnosed with DR from the National Health and Nutrition Examination Survey (NHANES) database, spanning the period from 2005 to 2008. The severity of DR was defined according to Early Treatment for Diabetic Retinopathy Study (ETDRs). The effect of NLR, PLR, SII, and RDW on proliferative diabetic retinopathy (PDR) were explored using multivariable logistic regression analysis model. Subgroup analysis and restricted cubic splines (RCS) were conducted to assess the robustness of the correlations across subgroups and to explore nonlinear relationships between four indices and PDR. The receiver operating characteristic (ROC) analysis was employed for the purpose of assessing and evaluating the predictive efficacy of NLR, PLR, SII, and RDW in determining the severity of DR. RESULTS: After adjusting for other confounders (age, gender, race, body mass index, diabetes duration, and HbA1c) in multivariable analysis, a unit increase of PLR×0.1, SII×0.01, and RDW would raise the risk for PDR by 15.6%, 22.2%, and 33%, respectively. Particularly, there was a 2.208-fold greater risk of PDR in individuals with an elevated NLR (OR=2.208, 95%CI, 1.348-3.617, P<0.001). RCS analyses showed positive relationships of four indices and PDR after segmented regression based on their own turning points. The results of ROC analysis revealed that PLR+RDW [area under the curve (AUC)=0.772, 95%CI: 0.669-0.874] had the best predictive value for PDR, compared with NLR+PLR+SII (AUC=0.697, 95%CI: 0.570-0.825) or RDW alone (AUC=0.736, 95%CI: 0.646-0.826). CONCLUSION: The combination of RDW and NLR demonstrates a promising ability to predict the severity of DR across the United States population, and it could be promisingly used in clinics for monitoring the progress of DR.