Genistein (G) and resveratrol (R) individually inhibit adipogenesis in 3T3-L1 adipocytes and induce apoptosis in cancer cells. We investigated whether the combination of G and R resulted in enhanced effects on adipogenesis, lipolysis, and apoptosis in 3T3-L1 cells. Preadipocytes and mature adipocytes were treated with G and R individually at 50 and 100 mmol/L (G100; R100) and in combination. Both in preadipocytes and mature adipocytes, G and R individually decreased cell viability dose-dependently, but G100 1 R100 further decreased viability by 59 ± 0.97% (P < 0.001) and 69.7 ± 1.2% (P < 0.001) after 48 h compared with G100 and R100, respectively. G100 + R100 induced apoptosis 242 ± 8.7% (P < 0.001) more than the control after 48 h, whereas G100 and R100 individually increased apoptosis only 46 ± 9.2 and 46 ± 7.9%, respectively. G and R did not modulate mitogen-activated protein kinase expression by themselves, but G100 + R100 increased Jun-N-terminal kinase phosphorylation by 38.8 ± 4.4% (P < 0.001) and decreased extracellular signal-regulating kinase phosphorylation by 48 ± 3.4% (P < 0.001). Individually, G and R at 25 μmol/L (G25; R25) decreased lipid accumulation by 30 ± 1.7% and 20.07 ± 4.27%, respectively (P < 0.001). However, G25 + R25 decreased lipid accumulation by 77.9 ± 3.4% (P < 0.001). Lipolysis assay revealed that neither G25 nor R25 induced lipolysis, whereas G25 + R25 significantly increased lipolysis by 25.5 ± 4.6%. The adipocyte-specific proteins PPARγ and CCAAT/enhancer binding protein-alpha were downregulated after treatment with G + R, but no effect was observed with individual compounds. These results indicate that G and R in combination produce enhanced effects on inhibiting adipogenesis, inducing apoptosis, and promoting lipolysis in 3T3-L1 adipocytes. Thus, the combination of G and R is more potent in exerting antiobesity effects than the individual compounds. © 2007 American Society for Nutrition.