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The end-stage immunopathology of type 1 diabetes resulting in β-cell destruction appears to be strongly dominated by cytotoxic CD8 T lymphocytes (CD8 T cells). However, the mechanism of cytotoxicity used by autoreactive CD8 T cells in the human setting remains unknown. Using type 1 diabetes patient–derived preproinsulin-specific CD8 T-cell clones recognizing either an HLA-A2 (A*0201) or HLA-A24 (A*2402)-restricted epitope (peptide of preproinsulin [PPI]_15–24, ALWGPDPAAA; or PPI_3–11, LWMRLLPLL), we assessed the use of conventional mediators of cytotoxicity in the destruction of human β-cells in vitro compared with virus-specific cytotoxic CD8 T-cell clones. We show that PPI-specific CD8 T-cell clones are mainly reliant upon cytotoxic degranulation for inducing β-cell death. Furthermore, we find that in comparison with virus-specific CD8 T cells, there are differences in the killing potency of PPI …