People are exposed to heavy metals in many ways during the course of their daily life. However, the effect of mixtures of heavy metals on mortality in the U.S. general population is unclear. We aimed to investigate the association between heavy metal concentrations (blood [lead, cadmium and mercury] and urine [barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, titanium, tungsten and uranium]) and all-cause, cardiovascular disease (CVD) and cancer mortality. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2014. Poisson regression was performed to analyze the associations between single-metal and multimetal exposure and mortality. The following variables were adjusted as covariates: demographic variables (age, education, sex and ethnicity), anthropometric variables (body mass index), lifestyle variables (family income, serum cotinine category and physical activity) and medical comorbidities (CVD and diabetes). A total of 26,056 subjects from the NHANES were included in the present study (mean follow-up, 7.4 years). The age of the participants ranged from 20 to 85 years. The blood metal mixture was associated with all-cause mortality (RR = 1.38, 95% CI 1.25, 1.51), CVD mortality (RR = 1.43, 95% CI 1.06, 1.94) and cancer mortality (RR = 1.41, 95% CI 1.12, 1.76) and cadmium had the highest weight in the weighted quantile sum (WQS) regression for all associations. The urinary metal mixture was associated with an increased risk of all-cause (RR = 1.48, 95% CI 1.30, 1.68) and cancer mortality (RR = 1.60, 95% CI 1.02, 2.52). Sex differences were found in the associations of both blood and urine metal mixtures with cancer mortality. Our study suggests a potential positive association for the concentrations of heavy metal mixtures with overall, CVD and cancer mortality based on a large sample of the U.S. general population. Nevertheless, further studies are needed to confirm these important findings. (c) 2020 Elsevier Ltd. All rights reserved.