Background: Platelets play an important role in pathogenesis of acute coronary syndromes and platelet parameters (platelet count[PC], mean platelet volume[MPV], and platelet distribution width[PDW]) have been proposed as risk factors for cardiovascular disease. Our aim was to examine the association of platelet parameters with all-cause and cardiovascular (CV) mortality in a large US cohort. Methods: We used the Third National Health and Nutrition Examination Survey and the data linked to mortality files to examine association between platelet parameters and all-cause and CV mortality. We used Cox proportional hazards model to calculate hazards ratio (HR) and 95% confidence interval (CI) using age as time-scale in 13,701 participants who were > 20 and <85 years and were free of clinical CV disease at baseline. Results: There were 2741 all-cause deaths and 1084 CV deaths during the follow-up (median follow-up 14.3 years, range 0 to 18). The mean (SD) age of the participants was 45 (18) years, 54% were females, 40% were Caucasians, 26% were current smokers and 24% had history of hypertension. Mean (SD) PC was 276(71) 10 9 /L, MPV 8.5(1.0) fL, and PDW 16.4% (0.56). Univariate analyses found no association of PC or MPV with all-cause or CV mortality but a significant association with PDW (all-cause mortality HR: 1.12 per unit increase in PDW, 95%CI: 1.03 to 1.21; CV mortality HR: 1.15, 95%CI: 1.01 to 1.31). Similarly, in multivariable analyses after adjusting for sex, race, CRP, diabetes, hypertension, smoking status, glomerular filtration rate, total cholesterol, WBC count, liver function tests, and ferritin, there was no association between PC or MPV and all-cause or CV mortality but the association with PDW remained significant (all-cause mortality HR: 1.16, 95%CI: 1.07 to 1.26 and HR for CV mortality: 1.17, 95%CI: 1.02 to 1.33. Conclusions: Among the platelet parameters, we found PDW, and not PC or MPV, as an independent predictor of all-cause and CV mortality. We propose that this test should be routinely reported with other hematological parameters in complete blood count reports.