Background: We examined the association between metabolic dysregulation and cancer mortality in a prospective cohort of Black and White adults. Methods: A total of 25,038 Black and White adults were included in the analysis. Metabolic dysregulation was defined in two ways: 1) using the joint harmonized criteria for metabolic syndrome (MetS) and 2) based on factor analysis of 15 variables characterizing metabolic dysregulation. We estimated hazards ratios (HRs) and 95% confidence intervals (CIs) for the association of MetS and metabolic dysregulation with cancer mortality during follow-up using Cox proportional hazards models. Results: About 46% of Black and 39% of White participants met the criteria for MetS. Overall, participants with MetS (HR: 1.22, 95% CI: 1.03-1.45) were at increased risk of cancer-related death. In race-stratified analysis, Black participants with MetS had significantly increased risk of cancer mortality compared with those without MetS (HR: 1.32, 95% CI: 1.01-1.72), increasing to more than a 2-fold risk of cancer mortality among those with five metabolic syndrome components (HR: 2.35, 95% CI: 1.01-5.51). Conclusions: There are marked racial differences in the prevalence of metabolic dysregulation defined as MetS based on the harmonized criteria. The strong positive associations between MetS and cancer mortality suggests that efforts to improve cancer outcomes in general, and racial disparities in cancer outcomes specifically, may benefit from prevention and management of MetS and its components.