The HLA class I allele HLA-A*33:03 is a risk factor for ticlopidine-induced liver injury. Herein, we show HLA class I-restricted ticlopidine-specific CD8+ T-cell activation in healthy donors expressing HLA-A*33:03. Cloned CD8+ T-cells proliferated and secreted IFN-γ in the presence of ticlopidine and autologous antigen presenting cells. A reduction of the T-cell response after blocking with HLA-class I and HLA-A*33 antibodies indicates that the interaction between drugs and the HLA allele detected in genetic association studies may be important for T-cell activation.