Resveratrol and its dimer ε-viniferin are polyphenolic compounds in red wine. Although various beneficial functions of resveratrol have been identified, those of ε-viniferin remain unclear. The present study therefore compared the effects of ε-viniferin and resveratrol on the differentiation of 3T3-L1 preadipocytes. We found that ε-viniferin more effectively suppressed intracellular lipid accumulation than resveratrol. ε-Viniferin, but not resveratrol, reduced protein expression of PPARγ and fatty acid synthase that contribute to lipogenesis, and increased expression of adipose triglyceride lipase, a lipolytic enzyme. Adiponectin protein expression, which plays a critical role in preventing type 2 diabetes and metabolic syndrome, was enhanced only by ε-viniferin. In addition, only ε-viniferin raised SIRT1 expression with increased phosphorylation of AMPK. These findings suggest that ε-viniferin is more effective than resveratrol in promoting favorable adipocyte differentiation with enhanced adiponectin expression and decreased lipid accumulation. Therefore, ε-viniferin may be a candidate phytochemical in red wine for preventing obesity.