Intravenous immunoglobulin (IVIg) is successfully used in the treatment of autoimmune diseases involving self-reactive CD8(+) T cells. However, its direct influence on the cytotoxic response remains unknown. Using an antigen cross-presentation assay and a mouse model of ovalbumin (OVA) immunization, we showed that IVIg decreases the in vitro activation, proliferation and cytokine secretion of OVA-specific CD8(+) T cells (OT-I), as well as the in vivo generation of OVA-specific CD8(+) T cells. In addition, IVIg significantly decreases the proportion of perforin- and CD107a-expressing CD8(+) T cells, and inhibits the cytotoxic activity of OVA-activated OT-I cells. The interference of IVIg with the CD8(+) T-cell response is associated with T-cell receptor blockade, therefore reducing the interaction between effector and target cells. A similar blockade is observed on human CD8(+) T cells, suggesting that the observations reported here could apply to the IVIg-mediated improvement of CD8(+) T-cell-mediated autoimmune conditions in human patients.