Pullulan and chitosan are biocompatible polysaccharides obtained from natural sources with many biomedical applications. Cationically modified polymers, such as chitosan and pullulan after covalent attachment of glycidyltrimethylammonium chloride (GTMAC), showed beneficial biological properties. In the present study, it was clearly demonstrated and confirmed that both cationically modified polysaccharides (chitosan-GTMAC and pullulan-GTMAC) have the antiatherosclerotic potential by inhibition of atherosclerotic plaque development and controlling the expression of genes involved in lipid metabolism. It has also been shown that the cationically modified chitosan (HTCC) at a dose of 200 mg/kg b.w./day in male apoE-knockout mice acted as hypolipidaemic agent. It was observed that a statistically significant decrease in low-density lipoprotein (LDL) cholesterol level by 32% occurred under the influence of HTCC at a dose of 200 mg/kg b.w./day after 16 weeks of the experiment compared to the control group of apoE(-/-) mice. Moreover, under the influence of cationically modified chitosan administered orally to female apoE-knockout mice at a dose of 300 mg/kg b.w./day for 18 weeks a statistically significant reduction by 33% in the area of atherosclerotic plaque was observed compared to the control group, i.e., apoE-knockout mice whose diet was not supplemented with the cationically modified polysaccharide. Current in vivo studies connected with cationically modified pullulan showed a statistically significant 22% reduction of the area of atherosclerotic plaque in the apoE(-/-) mice fed with a feed containing Pull-GTMAC at a dose of 500 mg/kg b.w./day for 18 weeks in comparison to the control group of apoE-knockout mice. In the in vitro studies it was also shown that cationically modified chitosan acted therapeutically by reduction of the level of the expression of human 3-hydroxy-3-methylglutaryl-CoA reductase (human HMG-CoAR) after 24 hours of incubation with HepG2 cells. However, cationically modified pullulan did not show this effect in the experiment on HepG2 cell line. On the other hand, Pull-GTMAC caused a statistically significant increase in insulin induced gene 1 (INSIG1) expression and increase in mRNA level of LDL receptor in brown fat tissue of female apoE-knockout mice after oral administration with feed at a dose of 300 mg/kg b.w./day for 18 weeks in comparison to the control group of apoE(-/-) mice, that was crearly demonstrated the effect of cationically modified pullulan on the expression of lipid metabolism genes in in vivo conditions. In the present article we have shown for first time that cationically modified pullulan and chitosan have some similarities in their antiatherogenic action but there are also some minor differences in mechanism of their effect on lipid metabolism.