OBJECTIVE: To evaluate whether telomerase activity, measured in circulating blood leukocytes, might be associated with prevalent atherosclerosis, or predict future coronary artery disease risk. METHODS AND RESULTS: We examined associations of telomerase activity levels measured at year 15 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study with prevalent coronary artery calcium (CAC), progressive CAC at year 20, and incident CAC between years 15 and 20, in 440 black and white men aged 33-45 years. Telomere length was also measured in a subset of participants (N=129). In age-adjusted analyses, higher telomerase activity levels were associated with black race/ethnicity, lower socioeconomic status, higher C-reactive protein levels, and smoking. In multivariate-adjusted analysis, higher quartiles of telomerase were cross-sectionally associated with greater odds of prevalent CAC at year 15 (quartile 2: OR=1.32, 95% CI: 0.54-3.23; quartile 3: OR=1.40, 95% CI: 0.60-3.30; quartile 4: OR=3.27, 95% CI: 1.39-7.71 compared with quartile 1, p-continuous=0.012) and progressive CAC at year 20, but telomerase was not significantly associated with incidence of newly detectable CAC. Higher telomerase activity levels predicted greater CAC progression at year 20 among persons with short telomere length; low telomerase and short TL predicted less CAC progression. CONCLUSION: Telomerase activity in leukocytes was associated with calcified atherosclerotic plaque, and was also a predictor of advancing plaque among persons with short telomeres.