Although cannabinoids are associated with antineoplastic activity in a number of cancer cell types, the effect in gastric cancer cells has not been clarified. In the present study, we investigated the effects of a cannabinoid agonist on gastric cancer cell proliferation and invasion. The cannabinoid agonist WIN 55,212-2 inhibited the proliferation of human gastric cancer cells in a dose-dependent manner and that this effect was mediated partially by the CB(1) receptor. We also found that WIN 55,212-2 induced apoptosis and down-regulation of the phospho-AKT expression in human gastric cancer cells. Furthermore, WIN 55,212-2 treatment inhibited the invasion of gastric cancer cells, and down-regulated the expression of MMP-2 and VEGF-A through the cannabinoid receptors. Our results open the possibilities in using cannabinoids as a new gastric cancer therapy. (c) 2010 Wiley-Liss, Inc.