This study examined the relationships of high-density lipoprotein cholesterol (HDL-C) with LTL and the rate of its shortening. Diminished levels of HDL-C are associated with an increased risk for atherosclerosis. Shortened leukocyte telomere length (LTL) also entails an increased atherosclerotic risk. We studied 472 Whites and 190 African Americans (AfAs) enrolled in the Bogalusa Heart Study. Subjects were examined serially 3-13 times for HDL-C over an average period of 27.8 years from childhood through young adulthood. LTL was measured twice during adulthood at a mean age of 31.5 years (baseline exam) and 37.8 years (follow-up exam). HDL-C trajectories with age were constructed and the area under the curve (AUC) was used as a measure of cumulative HDL-C levels. Multivariate regression analyses showed that LTL was positively associated with HDL-C in childhood (regression coefficient (bp per mg/dL) beta=3.1, p=0.024), adulthood (beta=4.4, p=0.058) and AUC from childhood to adulthood (beta=12.2, p=0.0004) in the combined sample of AfAs and Whites. The association between LTL and HDL-C AUC was stronger in females (beta=18.5, p<0.001) than in males (beta=2.9, p=0.590) (difference in slopes p=0.037). A slower rate of LTL shortening per year was associated with higher HDL-C AUC in the total sample (p=0.033), adjusting for baseline LTL. As HDL-C exerts anti-oxidant and anti-inflammatory effects and LTL registers the accruing burden of oxidative stress and inflammation, the association between HDL-C and LTL might be explained by the lifelong status of oxidative stress and inflammation.