We assessed the role of lead and cadmium as partial mediators between smoking and composite cardiovascular and cerebrovascular disease (CCVD). We also studied the association between urinary heavy metals and CCVD. Pooled data from NHANES 1999-2006 were examined. Cardiovascular and cerebrovascular disease was determined using a standardized questionnaire asking about history of stroke, angina, heart attack, coronary artery disease, and congestive heart failure. Increasing serum cadmium levels were associated with increasing prevalence of CCVD (P-trend: .03). Adjusted odds-ratio (OR) for active smokers versus never smokers was 2.09 (1.67-2.63). Adjustment for lead did not affect the OR but adjustment for cadmium significantly attenuated the OR (1.54 [1.17-2.03]). Significant association was observed between CCVD and urinary antimony, cadmium, cobalt, and tungsten. High levels of serum cadmium (>0.61 µg/L) were associated with CCVD. The relationship between smoking and CCVD was partially mediated through cadmium. Urinary antimony, cadmium, cobalt, and tungsten may be associated with CCVD.