Although prospective studies suggest that low selenium is a risk factor for cardiovascular disease, most clinical trials of selenium supplementation have not shown this benefit. Prospective studies of renal insufficiency show that it is associated with low-selenium levels, and increased cardiovascular disease risk. We hypothesized that low selenium and renal insufficiency might show biologically important interactions warranting a future trial of selenium supplementation in this high-risk group of patients with both renal insufficiency and low selenium. We evaluated the prospective association of low selenium and renal insufficiency with coronary heart disease and all-cause mortality. A cohort of 10,531 NHANES III participants aged 35 years or older with serum selenium measurements and creatinine were followed longitudinally and linked to the National Death Index. In multivariable-adjusted analysis, low-selenium levels were associated with an increased risk of CHD mortality (HR=1.26; 95% CI: 0.94-1.69) and an increased risk for all-cause mortality (HR=1.41; 95% CI: 1.18-1.68). Renal insufficiency was also associated with increased risk of CHD mortality (HR=1.64; 95% CI: 1.29-2.08) and all-cause mortality (HR=1.51; 95% CI: 1.31-1.74). Despite the findings that adults with impaired renal function and low selenium had an increased risk for CHD mortality (HR=2.06; 95% CI: 1.13-3.75), there was no evidence of supra-additivity between low selenium and renal insufficiency on rate of CHD mortality (relative excess risk due to the interaction [RERI=0.16; 95% CI: -1.34 to 1.65] or all-cause mortality (RERI=-0.85; 95% CI: -1.50 to -0.20). This analysis suggests that the combination of renal insufficiency and low selenium does not represent an extremely high-risk group where a randomized trial of selenium supplementation would be of greater value than focusing on all adults with low-serum selenium.