Serum 25-hydroxyvitamin D₃ [25(OH)D₃] concentrations have been associated with diabetic retinopathy (DR) severity. Blood cadmium has also been reported to be associated with the presence of DR. Besides, cadmium can decrease the formation of calcitriol (active vitamin D) in blood. However, the effect of blood cadmium on the association between 25(OH)D₃ and DR severity has not been studied comprehensively. Therefore, we designed this cross-sectional study to assess the effect modification of blood cadmium on the association between 25(OH)D₃ and DR severity in the U.S. population with type 2 diabetes (T2D). This study was conducted using NHANES from 2005 to 2008. By having stratified participants based on blood cadmium category (low blood cadmium<2.76 nmol/L; high blood cadmium≥2.76 nmol/L), we evaluated the difference (interaction test) between the relationship of 25(OH)D₃ with the severity of DR among low blood cadmium and high blood cadmium participants using multivariable logistic regression. In this cross-sectional study, a total of 283 participants were included. In the high blood cadmium group, the odds ratio for severe non-proliferative retinopathy (NPDR)/proliferative retinopathy (PDR) of high 25(OH)D₃ (≥50 nmol/L) group was 0.26 (95% CIs: 0.09–0.69, p=0.01) compared with the reference group (low 25(OH)D₃ group). Furthermore, there was evidence of interaction between 25(OH)D₃ and blood cadmium on decreasing the incidence of severe NPDR/PDR. Our study indicated that blood cadmium might affect the association of 25(OH)D₃ with DR severity in participants with T2D. More randomized controlled trials are needed to provide more evidence of such a finding.