Objective: Telomerase Reverse Transcriptase (TERT), the catalytic subunit of telomerase, supports critical cellular responses required for tissue remodeling. Previous studies established that TERT expression is induced in activated macrophages and during experimental and human atherosclerosis formation. In the present study, we investigated the role of TERT for atherosclerosis development and macrophage inflammation. Approach and Results: TERT-deficient mice were crossbred with LDL-receptor-deficient (LDLr-/-) mice to generate first generation G1TERT-/-LDLr-/- offsprings, which were then further intercrossed to obtain third generation G3TERT-/-LDLr-/- mice. G1TERT-/-LDLr-/- mice revealed no telomere shortening while severe telomere attrition was evident in G3TERT-/-LDLr-/- mice. When fed an atherogenic diet, G1TERT-/-LDLr-/- and G3TERT-/-LDLr-/- mice were both protected from atherosclerosis formation compared to their wildtype controls, indicating that genetic TERT-deletion prevents atherosclerosis, and formation of the disease is not affected by telomere attrition. Similarly, atherosclerosis development was decreased in chimeric LDLr-/- mice with TERT deletion in hematopoietic stem cells after bone marrow transplantation. TERT deficiency reduced macrophage accumulation in atherosclerotic lesions and altered chemokine expression, including CXC1/2/3, CCL3, CCL5, CCL21, CCR7, IL-6, and IL-1α. In isolated macrophages, sequence analysis of silenced inflammatory gene promoters indicated that TERT deletion altered signal transducer and activator of transcription 3 (STAT3)-dependent chemokine expression and recruitment of phosphorylated STAT3 to its target promoters. Mechanistically, TERT expression was necessary and sufficient to maintain STAT3 phosphorylation. Finally, we demonstrate that TERT deletion induces transcription of PIAS and SOCS3, both are endogenous inhibitors of STAT3 pathway. Conclusions: We propose that genetic TERT deficiency decreases atherosclerosis formation by silencing inflammatory chemokine transcription through inactivation of the STAT3 signaling pathway.