We evaluated the mechanism of recognition of myeloma cells by gamma delta T cells. The expanded gamma delta T cells killed RPMI8226 and U266 myeloma cells in a gamma delta T-cell dose-dependent manner. Pretreatment of myeloma cells with zoledronic acid or mevastatin showed that gamma delta T cells kill myeloma cells by recognizing the mevalonate metabolites. The expression level of intercellular cell adhesion molecule-1 (ICAM-1) on myeloma cells correlates with the cytotoxicity by gamma delta T cells. Pretreatment of RPMI8226 and U266 with an anti-ICAM-1 monoclonal antibody inhibited their cytolysis. Moreover, AMC-1 myeloma cells transfected with of human ICAM-1 cDNA were susceptible to gamma delta T cells compared to parental AMO-1 cells. In conclusion, gamma delta T cells recognize the mevalonate metabolites and ICAM-1 on myeloma cells. (c) 2007 Elsevier Inc. All rights reserved.