OBJECTIVE: To examine if the association between higher A1C and risk of cardiovascular disease (CVD) among adults with and without diabetes is modified by racial residential segregation. RESEARCH DESIGN AND METHODS: The study used a case-cohort design, which included a random sample of 2,136 participants at baseline and 1,248 participants with incident CVD (i.e., stroke, coronary heart disease [CHD], and fatal CHD during 7-year follow-up) selected from 30,239 REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants originally assessed between 2003 and 2007. The relationship of A1C with incident CVD, stratified by baseline diabetes status, was assessed using Cox proportional hazards models adjusting for demographics, CVD risk factors, and socioeconomic status. Effect modification by census tract-level residential segregation indices (dissimilarity, interaction, and isolation) was assessed using interaction terms. RESULTS: The mean age of participants in the random sample was 64.2 years, with 44% African American, 59% female, and 19% with diabetes. In multivariable models, A1C was not associated with CVD risk among those without diabetes (hazard ratio [HR] per 1% [11 mmol/mol] increase, 0.94 [95% CI 0.76-1.16]). However, A1C was associated with an increased risk of CVD (HR per 1% increase, 1.23 [95% CI 1.08-1.40]) among those with diabetes. This A1C-CVD association was modified by the dissimilarity (P < 0.001) and interaction (P = 0.001) indices. The risk of CVD was increased at A1C levels between 7 and 9% (53-75 mmol/mol) for those in areas with higher residential segregation (i.e., lower interaction index). In race-stratified analyses, there was a more pronounced modifying effect of residential segregation among African American participants with diabetes. CONCLUSIONS: Higher A1C was associated with increased CVD risk among individuals with diabetes, and this relationship was more pronounced at higher levels of residential segregation among African American adults. Additional research on how structural determinants like segregation may modify health effects is needed.