Background: Uterine fibroids (UF) affect 77% of women by menopause, and account for $ 9.4 billion in annual healthcare costs. Type-2-diabetes (T2D) has inconsistently associated with protection from UFs in prior studies. To further evaluate the relationship between T2D and UFs we tested for association between T2D and UF risk in a large clinical population as well as the potential differences due to T2D medications and interaction with race. Methods: This nested case-control study is derived from a clinical cohort. Our outcome was UF case-control status and our exposure was T2D. UF outcomes and T2D exposure were classified using validated electronic medical record (EMR) algorithms. Logistic regression, adjusted for covariates, was used to model the association between T2D diagnosis and UF risk. Secondary analyses were performed evaluating the interaction between T2D exposure and race and stratifying T2D exposed subjects by T2D medication being taken. Results: We identified 3,789 subjects with UF outcomes (608 UF cases and 3,181 controls), 714 were diabetic and 3,075 were non-diabetic. We observed a nominally significant interaction between T2D exposure and race in adjusted models (interaction p = 0.083). Race stratified analyses demonstrated more protection by T2D exposure on UF risk among European Americans (adjusted odds ratio [ aOR] = 0.50, 95% CI 0.35 to 0.72) than African Americans (aOR = 0.76, 95% CI 0.50 to 1.17). We also observed a protective effect by T2D regardless of type of T2D medication being taken, with slightly more protection among subjects on insulin treatments (European Americans aOR = 0.42, 95% CI 0.26 to 0.68; African Americans aOR = 0.60, 95% CI 0.36 to 1.01). Conclusions: These data, conducted in a large population of UF cases and controls, support prior studies that have found a protective association between diabetes presence and UF risk and is further modified by race. Protection from UFs by T2D exposure was observed regardless of medication type with slightly more protection among insulin users. Further mechanistic research in larger cohorts is necessary to reconcile the potential role of T2D in UF risk.