Although low level of high-density lipoprotein (HDL) cholesterol inversely corelates with atherosclerotic cardiovascular disease (ASCVD) risk, there is an increasing awareness that HDL quality may be more important than HDL quantity. Low activity of liver-derived HDL associated paraoxonase 1 (PON1), which determines the antioxidant and antiatherosclerotic capabilities of HDL, is considered to be novel nontraditional risk factor for development of ASCVD. The aim of this study was to determine whether the antiatherogenic properties of incretin-based antidiabetic drugs may be related to their ability to impact on HDL-PON1 activity and expression in the fructose-fed rats. Control and fructose-fed (8 wk) rats were treated (4 wk) with exenatide (5.0/10.0 μg/kg s.c.) or sitagliptin (5.0/10 mg/kg p.o.). Plasma and liver PON1 activity was measured calorimetrically. Plasma PON1 protein was determined by ELISA. Liver PON1 protein and mRNA expression were assayed by Western blot and real-time PCR, respectively. Unexpectedly, chronic exenatide administration into fructose-fed rats at low and high dose reduced PON1 arylesterase activity (P < 0.001) and decreased plasma enzyme concentration (P < 0.001), without affecting plasma PON1 paraoxonase and thiolactonase activity. In the liver a high dose of exenatide reduced PON1 protein expression (P < 0.001) without affecting PON1 gene expression. Whereas sitagliptin in these animals had no effect on plasma PON1 activity and concentration as well as on liver activity and expression of the enzyme. The known anti-atherosclerotic effect of incretin drugs is not related to their positive effect on PON1 activity and expression.