Atherosclerosis being the main cause of myocardial infarction and stroke remains a global medical and social problem. Despite the fact that it is recognized as a chronic inflammatory disorder, the intracellular molecular mechanisms that drive the disease progression are poorly understood. The CDK8 and CDK19 cyclindependent kinases being the key regulators of transcription and inflammation can potentially play an important role in the atherosclerosis pathogenesis. The study aimed to assess the impact of the Cdk8 and Cdk19 gene knockout on the development of atherosclerotic lesions in apolipoprotein E-deficient mice (ApoE⁻/⁻). It has been shown that both endothelium-specific and systemic Cdk8 knockout significantly reduce the area of atherosclerotic aortic lesions, and the total knockout has a more prominent anti-atherogenic effect. This suggests a pleiotropic role of CDK8 in the atherosclerosis pathogenesis mediated by its function not only in endothelial cells, but probably also in macrophages. In contrast to Cdk8, the systemic Cdk19 knockout had no significant effect on the development of atherosclerosis. Thus, CDK8, but not CDK19, has been identified as a pro-atherogenic regulator, which makes it a promising target for the development of novel therapeutic strategies.