Curcumin has diverse biological activities, but is known to undergo rapid metabolism via reduction of vinylic double bonds and phase II conjugation. To prevent reductive metabolism of curcumin, we introduced a methyl group at both C2 and C6 positions (compound1) or at the C2 position (compound2) of curcumin, creating steric hindrance on double bonds against metabolizing enzymes. As predicted, these compounds were resistant to reduction by alcohol dehydrogenase. Compound1was further evaluated for its antiangiogenesis activityin vitroandin vivo. It exhibited significantly greater inhibitory activity than curcumin against endothelial cell migration, invasion and tube formation. Similarly, thein vivoMatrigel plug assay in C57BL/6 mice showed more pronounced reduction of blood vessels in the plugs containing1than those containing curcumin. Moreover,1suppressed tumor growth more effectively than curcumin in a U87MG mouse xenograft model by inhibiting angiogenesis.In vivometabolite analysis by liquid chromatography/mass spectrometry demonstrated that1underwent markedly slower reductive metabolism than curcumin. Taken together, our results indicate that1has enhanced antiangiogenesis activity and suppression of tumor growth compared with curcumin, reflecting diminished reductive metabolism owing to the introduction of methyl groups at the C2 and C6 positions of curcumin.