Bisphosphonates are well-known inhibitors of osteoclastic bone resorption, but recent clinical reports support the possibility of direct or indirect antitumor effects by these compounds. Because bisphosphonates share structural homologies with recently identified gamma delta T-cell ligands, we examined the stimulatory capacity of bisphosphonates to gamma delta T cells and determined whether gamma delta T-cell stimulation by bisphosphonates could be exploited to generate antiplasma cell activity in multiple myeloma (MM). All tested aminobisphosphonates (alendronate, ibandronate, and pamidronate) induced significant expansion of gamma delta T cells (V gamma 9V delta 2++ subset) in peripheral blood mononuclear cell cultures of healthy donors at clinically relevant concentrations (half-maximal activity, 0.9-4 mcmol/L). The proliferative response of gamma delta T cells to aminobisphosphonates was IL-2 dependent, whereas activation of gamma delta T cells (up-regulation of CD25 and CD69) occurred in the absence of exogenous cytokines. Pamidronate-activated gamma delta T cells produced cytokines (ie, interferon [IFN]-gamma) and exhibited specific cytotoxicity against lymphoma (Daudi) and myeloma cell lines (RPMI 8226, U266). Pamidronate-treated bone marrow (BM) cultures of 24 patients with MM showed significantly reduced plasma cell survival compared with untreated cultures, especially in cultures in which activation of BM-gamma delta T cells was evident (14 of 24 patients with MM). gamma delta T-cell depletion from BM cultures completely abrogated the cytoreductive effect on myeloma cells in 2 of 3 tested patients with MM. These results show that aminobisphosphonates stimulating gamma delta T cells have pronounced effects on the immune system, which might contribute to the antitumor effects of these drugs. (Blood. 2000;96:384-392)