Objective— CXCL12 encodes stromal cell–derived factor 1α (SDF-1), which binds to the receptor encoded by CXCR4 . Variation at the CXCL12 locus is associated with coronary artery disease and endothelial progenitor cell numbers, whereas variation at the CXCR4 locus is associated with leukocyte telomere length, which has been shown to be associated with coronary artery disease. Therefore, we examined the relationships of plasma SDF-1 levels to cardiovascular disease (CVD)–related outcomes, risk factors, leukocyte telomere length, and endothelial progenitor cells. Approach and Results— SDF-1 was measured in 3359 Framingham Heart Study participants. We used Cox regression to examine relationships of SDF-1 to new-onset CVD, myocardial infarction, heart failure, and all-cause mortality; we used linear regression to evaluate associations of SDF-1 with risk factors, leukocyte telomere length, and CD34+ cell phenotypes. In multivariable models, higher SDF-1 levels were associated with older age, lower levels of high-density lipoprotein-cholesterol and cigarette smoking. Higher SDF-1 levels were associated with lower CD34+ cell frequency ( P =0.02) but not with leukocyte telomere length. During follow-up (median, 9.3 years), there were 263 new-onset CVD events, 160 myocardial infarctions, 200 heart failure events, and 385 deaths. After adjusting for clinical risk factors, SDF-1 levels were associated with heart failure ( P =0.04) and all-cause mortality ( P =0.003) but not with CVD ( P =0.39) or myocardial infarction ( P =0.10). The association of SDF-1 levels with myocardial infarction was attenuated after adjustment for high-density lipoprotein-cholesterol. Conclusions— After adjusting for traditional CVD risk factors, SDF-1 is associated with heart failure and all-cause mortality risk. Additional studies are needed to determine whether measurement of SDF-1 levels has clinical use.