gamma delta T-cells have been implicated in the immunopathogenesis of multiple sclerosis (MS), possibly through interaction with heat shock proteins (hsp). We have previously demonstrated that human oligodendrocytes (OGC) express hsp on their surface and induce the proliferation and expansion of gamma delta T-cells. We also showed that gamma delta T-cells are highly cytolytic to OGC in vitro. The current study addresses whether gamma delta T-cell-induced cytotoxicity to OGC involves the recognition of hsp on OGC or some other ligand. We first compared the lytic potential for different human glial cells and found that gamma delta T-cells lysed OGC, microglia and human fetal astrocytes to the same extent, despite the preferential expression of hsp only on OGC. This suggested that either hsp was not involved in cytolytic recognition or that more than one ligand exists. To address this we used cell lines that either shared OGC properties of hsp expression and the ability to stimulate gamma delta T-cells (RPMI 8226, Daudi) or did not (U937) in cold target competition assays with OGC. Results demonstrated that although all the cell lines were effectively killed by gamma delta T-cells, only the RPMI 8226 and Daudi cells were able to effectively compete for lysis with the OGC. These results support the notion that probably more than one ligand for gamma delta T-cell cytotoxic recognition exists but hsp could still be involved in gamma delta T-cell-induced lysis of OGC. Regulating the expression of hsp on OGC might therefore be a way of interfering with potential gamma delta T-cell-induced damage in MS.