Background Differences in death rate and cardiovascular disease (CVD) between Black and White patients with chronic kidney disease is attributed to sociocultural factors, comorbidities, genetics, and inflammation. Methods and Results We examined the interaction of race, plasma IL‐6 (interleukin‐6), and TMPRSS6 genotype as determinants of CVD and mortality in 3031 Chronic Renal Insufficiency Cohort study participants. The primary outcomes were all‐cause mortality and a composite of incident myocardial infarction, peripheral artery disease, stroke, and heart failure. During the median follow‐up of 10 years, Black patients with chronic kidney disease experienced a significantly higher mortality (34% versus 26%) and CVD composite (41% versus 28%) compared with White patients. After adjustment, TMPRSS6 genotype did not associate with the outcomes. The adjusted hazard ratio for mortality (4.11 [2.48–6.80], P <0.001) and CVD composite (2.52 [1.96–3.24], P <0.001) were higher for the highest versus lowest IL‐6 quintile. The adjusted hazards for death per 1‐quintile increase in IL‐6 in White and Black individuals were 1.53 (1.42–1.64) versus 1.29 (1.20–1.38) ( P <0.001), respectively. For CVD composite they were 1.61 (1.50–1.74) versus 1.30 (1.22–1.39) ( P <0.001), respectively. In Cox proportional hazard models that included IL‐6, there was no longer a racial disparity for death (1.01 [0.87–1.16], P =0.92), but significant unexplained mediation remained for CVD (1.24 [1.07–1.43]; P =0.004). Path models that included IL‐6, diabetes, and urine albumin to creatinine ratio were able to identify variables responsible for racial disparity in mortality and CVD. Conclusions Racial differences in mortality and CVD among patients with chronic kidney disease could be explained by good‐fitting path models that include selected mediator variables including diabetes and plasma IL‐6.