Paraoxonase-2 (PON-2) is an intracellular antioxidant enzyme that can be modulated by polyphenols. The aim of this study was to verify whether yerba mate (Ilex paraguariensis), a plant species rich in phenolic compounds, modulates gene expression and the activity of PON-2 in macrophages in vitro and in monocytes from peripheral blood and monocyte-derived macrophages obtained after the ingestion of green or roasted yerba mate infusions by healthy subjects.THP-1 macrophages were incubated with increasing amounts of yerba mate extracts or chlorogenic and caffeic acids (1-10 μmol/L). The in vivo effects of yerba mate or water (control) intakes were evaluated acutely (2 h after ingestion) and in the short term (after daily ingestion for 7 d) in 20 healthy women.In general, there was no difference between the two kinds of yerba mate studied. Yerba mate extracts or chlorogenic acid at 1 and 3 μmol/L increased PON-2 relative gene expression in THP-1 macrophages (P < 0.05), whereas higher concentrations (5 and 10 μmol/L) increased the activity only. Caffeic acid induced PON-2 activity only. The acute ingestion of yerba mate infusions increased relative gene expression and PON-2 activity in monocytes (P < 0.05), whereas the consumption of yerba mate for 7 d increased PON-2 relative gene expression (P < 0.05) and had a tendency to increase PON-2 activity in monocytes and monocyte-derived macrophages.It is suggested that green or roasted yerba mate modulates positively the mRNA relative expression and activity of the PON-2 enzyme in monocytes and macrophages, which may prevent cellular oxidative stress.