Matrix metalloproteinases (MMPs) play an important role in physiological and pathological matrix degradation. Here, we report that flavonoids, at physiologically relevant concentrations, inhibit two members of this enzyme family, namely MMP-2 and -9. Eight flavonoids with increasing number of hydroxy groups and other modifications were compared for their capacity to inhibit recombinant catalytic domains of these proteases. EC50 values ranged from 59 and 70 microM (primuletin/5-hydroxyflavone) to 9 and 4 microM (luteolin 7- O-glucoside) for MMP-2 and -9, respectively. Interestingly, the latter glucoside was an equal (MMP-2) or even stronger (MMP-9) inhibitor than its aglycone, luteolin. For luteolin, one of the strongest flavonoids tested, kinetic analysis revealed a non-competitive type of inhibition. Our results add a novel function to the long list of biological effects of these ubiquitous plant constituents that may contribute to and enhance their modulating influence on extracellular matrix degradation and remodelling.