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The human paraoxonase (<i>PON</i>) gene cluster is comprised of three contiguous genes (<i>PON1, PON2</i> and <i>PON3</i>) of presumably common origin coding three lactonases of highly similar structure and substrate specificity. The catalytic activity of PON proteins is directed toward artificial organophosphates and in physiological conditions toward thiolactones and oxidized phospholipids. Consequently, PON enzymes are regarded as an effective defense against oxidative stress and, as a result, against atherosclerosis development. Additionally, both PON’s serum activity and its concentration are influenced by several polymorphic variations in coding and noncoding DNA regions of the <i>PON</i> gene cluster remaining in linkage disequilibrium. Hence, the genetic polymorphism of the <i>PON</i> gene cluster may contribute to atherosclerotic process progression or deceleration. In this review the authors analyzed the relevance of noncoding DNA polymorphic variations of <i>PON</i> genes in atherosclerosis-related diseases involving coronary and peripheral artery disease, stroke, diabetes mellitus, dementia and renal disease and concluded that the effect of PON gene cluster’ polymorphism has a considerable impact on the course and outcome in these conditions. The following <i>PON</i> genetic variations may serve as additional predictors of the risk of atherosclerosis in selected populations and individuals.