Purpose <p>To investigate the significance of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI), as diagnostic and prognostic factors in patients with diabetic retinopathy (DR) in a cross-sectional study and longitudinal epidemiological investigation.</p> Methods <p>This study included a retrospective cross-sectional study and a longitudinal epidemiological investigation- the Beichen Eye Study (BCES). In the former study, 203 participants were enrolled from January 2021 to May 2022. Factors associated with DR were analyzed, and the receiver operating characteristic (ROC) curve analysis was also performed. 5840 subjects were enrolled in BCES. 479 individuals were diagnosed with diabetes mellitus (DM without DR) at baseline, of which 92 individuals developed DR over a 2-year follow-up. The effect of NLR, SII, SIRI, and other risk factors was explored on the incidence of DR.</p> Results <p>The cross-sectional study showed that patients with Proliferative DR (PDR) or Non-Proliferative DR (NPDR) had significantly higher levels of NLR, SII, and SIRI than DM without DR and control subjects. The combined index of NLR, SII, and SIRI improved AUC to 0.765 from 0.728 to 0.755 for individual indices in diagnosing DR. BCES reported that SIRI levels were significantly higher at baseline in individuals who went on to develop DR relative to the patients without progression during the 2-year follow-up. SIRI (&gt; 1.222) is associated with a 2.3-fold increased DR risk (<i>p</i> = 0.015), while further validation is needed.</p> Conclusion <p>NLR, SII, and SIRI are significantly increased in patients with DR. SIRI is an independent risk factor for the development of DR, highlights its potential as a predictive indicator for DR in routine screening.</p>