IntroductionWe examined whether metabolic health status increases the risk of cancer mortality, and whether this association varied by body mass index (BMI) category.MethodsWe performed a prospective study of 22,514 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We defined metabolic unhealthy status as having 3+ of the following: 1) elevated fasting glucose, 2) high triglycerides, 3) dyslipidemia, 4) hypertension, and 5) elevated waist circumference. We categorized participants into normal weight (BMI: 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2) and obese (BMI ≥ 30 kg/m2) groups. We performed Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for cancer mortality during follow-up.ResultsAmong participants with normal weight, those who were metabolically unhealthy had increased risk of cancer mortality (HR: 1.57; 95% CI: 1.15 – 2.16) compared with metabolically healthy participants. Overall mortality risk for participants who were metabolically unhealthy and normal-weight was stronger for obesity-related cancers (HR: 2.31, 95% CI: 1.13 – 4.73). Compared with participants with normal weight, those who were metabolically healthy overweight were at reduced risk of any cancer mortality (adjusted HR: 0.79, 95% CI: 0.63-0.98).ConclusionThere was an increased risk of overall- and obesity-related- cancer mortality among metabolically unhealthy normal weight participants.