BACKGROUND: Oxidative stress and mitochondrial dysfunction play an important role in diabetic retinopathy (DR), and serum methylmalonic acid (MMA) levels are related to oxidative stress and mitochondrial dysfunction. We aimed to explore the impact of MMA levels and the composite dietary antioxidant index (CDAI) on DR risk in patients with diabetes. METHODS: Data on patients with diabetes from the 1999-2004 and 2011-2014 National Health and Nutrition Examination Survey (NHANES) datasets were included in this cross-sectional study. Logistic regression analysis (accounting for NHANES survey weights) was used to explore the association of MMA (< 250, ≥ 250 nmol/L) and CDAI (>-0.5, ≤-0.5) with DR risk, and the association was reported as odds ratio (OR) and 95% confidence interval (CI). The combined effect of MMA and CDAI on DR risk was also explored. RESULTS: A total of 2,373 patients with diabetes were included and 547 (20.48%) patients had DR. MMA levels ≥ 250 nmol/L (OR = 1.47, 95%CI: 1.01-2.13) (vs. <250 nmol/L) were associated with higher odds of DR in patients with diabetes, whereas there was no significant difference in the effect of CDAI >-0.5 and CDAI ≤-0.5 on DR risk (P > 0.05). There was an interaction between MMA and CDAI that increased the risk of DR (OR = 2.24, 95%CI: 1.15-4.35; P=0.018), and this interaction was only in patients with a CDAI ≤-0.5. Subgroup analysis revealed that the interaction between MMA and CDAI was observed in patients < 65 years of age (OR = 5.43, 95%CI: 1.80-16.36), with a body mass index ≥ 25 kg/m (OR = 2.26, 95%CI: 1.11-4.61), with hypertension (OR = 2.13, 95%CI: 1.04-4.36), and with anti-diabetic drug use (OR = 2.42, 95%CI: 1.13-5.20). CONCLUSION: There is an interaction between MMA and CDAI that increases the risk of DR, and CDAI plays a moderating role in this association.