Whereas dyslipidemia has been associated with leukocytosis, the relationship between serum cholesterol and other hematopoietic lineages is poorly defined. Erythrocytes and platelets, anucleate cells relegated to nonspecific, diffusional exchange of cholesterol with serum, have been proposed to have a distinct relationship to cholesterol from leukocytes. We examined the relationship between serum cholesterol and circulating erythrocyte/platelet indices in 4,469 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2005-2006. In linear regression analyses, serum non-high density lipoprotein-cholesterol (non-HDL-C) was positively associated with mean erythrocyte number, hematocrit, hemoglobin concentration, platelet count, and platelet crit independently of age, gender, race/ethnicity, smoking, body mass index, serum folate, and C-reactive protein. The magnitude of the relationship was most marked for platelets, with lowest vs. highest non-HDL-C quartile subjects having geometric mean platelet counts of 258,000/μL vs. 281,000/μL, respectively (adjusted model, P<0.001 for trend). These associations persisted in a sensitivity analysis excluding several conditions that affect erythrocyte/platelet and/or serum cholesterol levels, and were also noted in an independent analysis of 5,318 participants from NHANES 2007-2008. As non-HDL-C, erythrocytes, and platelets all impact cardiovascular disease risk, there is a need for advancing understanding of the underlying interactions that govern levels of these three blood components.