Circulating blood CD34+ cells consist of hematopoietic stem/progenitor cells, angiogenic cells, and endothelial cells. In addition to their clinical use in hematopoietic stem cell transplantation CD34+ cells may promote therapeutic neovascularization. Thus, understanding factors that influence circulating CD34+ cell frequency has wide implications for vascular biology in addition to stem cell transplantation. We examined clinical and genetic characteristics associated with circulating CD34+ cell frequency in a large, community-based sample of 1,786 Framingham Heart Study participants. Among individuals without cardiovascular disease (n=1,595), CD34+ frequency was inversely related to older age, female sex, and smoking. CD34+ frequency was positively related to weight, serum total cholesterol, and statin therapy. Clinical covariates accounted for 6.3% of CD34+ variability. CD34+ frequency was highly heritable (h(2)= 54%; P<0.0001). Genome-wide association analysis of CD34+ frequency identified suggestive associations at several loci, including OR4C12 (chromosome 11; P=6.7x10(-7)) and ENO1 and RERE (chromosome 1; P=8.8x10(-7)). CD34+ cell frequency is reduced in older individuals, and is influenced by environmental factors including smoking and statin use. Notably, CD34+ frequency is highly heritable. These findings have implications for therapies that utilize CD34+ cell populations, and support efforts to better understand the genetic mechanisms that underlie CD34+ frequency.