Ginseng has made a successful transition from the world of traditional tonic remedies to conventional medicine, and since the 1920s ginseng root has been documented to be effective in diabetes, hypertension, dyslipidemia and obesity. Based on this wide spectrum of activity we wondered whether ginseng root extract might also be effective in metabolic syndrome (MetSyn). In a series of investigations to develop a potential anti-MetSyn agent, we prepared a vinegar-processed form of ginseng radix (ginsam, GS) and compared its anti-MetSyn effects to those of non-processed ginseng radix (GR) in an ICR mouse model of MetSyn induced by a high fat diet. GR- and GS-treated mice (500 mg/kg/day for 8 weeks) had an 81% and 90% decrease in insulin resistance respectively, compared to the high fat diet (HFD) control. White adipocyte size was dramatically reduced by 67% and 80% in GR- ahd GS-treated groups respectively, compared to the HFD fed control. This result was reflected by a marked inhibition of weight gain in GS-treated mice (GR vs. GS, 53% vs. 86%). Analysis of ginsenoside composition indicated that prosapogenin Rg3 might be responsible for the anti-MetSyn activity of GS. In conclusion, Vinegar-processed ginseng radix (GS) was found to have a significantly greater anti-MetSyn effect than ginseng radix, and we suggest that ginsam should be subjected to clinical trials in the future, and that the role of prosapogenin Rg3 in the anti-MetSyn effect of ginsam should be confirmed.