Xanthohumol (XN) and guggulsterone (GS) have each been shown to inhibit adipogenesis and induce apoptosis in adipocytes. In the present study effects of the combination of XN+GS on 3T3-L1 adipocyte apoptosis and adipogenesis were investigated. Mature adipocytes were treated with XN and GS individually and in combination. XN and GS individually decreased cell viability, but XN+GS caused an enhanced decrease in viability and potentiated induction of apoptosis. Likewise, XN+GS caused a potentiated increase in caspase-3/7 activation, whereas neither of the compounds showed any effect individually. In addition, western blot analysis revealed that XN+GS increased Bax expression and decreased Bcl-2 expression, whereas individual compounds did not show any significant effect. XN and GS both decreased lipid accumulation. Individually, XN at $1.5;{mu}M$ and GS at $3.12;{mu}M$ decreased lipid accumulation by $26;{pm};4.5%$ (P < .001) each, whereas XN1.5+GS3.12 decreased lipid accumulation by $78.2;{pm};1.8% (P < .001). Moreover, expression of the adipocyte-specific proteins was down-regulated with XN1.5+GS3.12, but no effect was observed with the individual compounds. Finally, XN+GS caused an enhanced stimulation of lipolysis. Thus, combination of XN and GS is more potent in exerting anti-obesity effects than additive effects of the individual compounds.