Here we report that genistein, a soybean isoflavone, strongly inhibits tumor promoter-induced H2O2 formation both in vivo and in vitro. Genistein suppressed H2O2 production by 12-O-tetradecanoylphorbol-13-acetate- (TPA) stimulated human polymorphonuclear leukocytes (PMNs) and HL-60 cells in a dose-dependent manner over the concentration range 1-150 microM. Human PMNs were more sensitive to the inhibitory effect of genistein than HL-60 cells (50% inhibitory concentration 14.8 and 30.2 microM, respectively). In addition, genistein moderately inhibited superoxide anion formation by HL-60 cells and scavenged exogenously added H2O2 under the same conditions as in cell culture. However, the H2O2-scavenging effect of genistein was about 50% lower than its inhibition of cell-derived H2O2 formation at all concentrations. In the CD-1 mouse skin model, genistein strongly inhibited TPA-induced oxidant formation, edema, and PMN infiltration in mouse skin. Inhibition of TPA-mediated H2O2 in vivo may result from decreased cell-derived H2O2 formation, scavenging of H2O2 produced, and/or suppression of PMN infiltration into the dermis. The antioxidant properties of genistein may be responsible for its anticarcinogenic effects, and the dietary availability of genistein makes it a promising candidate for the prevention of human cancers.