In sepsis, the liver plays a crucial role in regulating immune responses and is also a target organ for immune-related injury. Despite the critical function of CD8(+) T cells against opportunistic viral infections, the CD8 immune response in the liver during sepsis remains elusive. Here we found that Tim-3 is highly up-regulated in liver CD8(+) T cells in a mouse cecal ligation and puncture model and in peripheral blood CD8(+) T cells of human patients with sepsis. The expression of Tim-3 in liver CD8(+) T cells displayed a bi-phasic pattern and deletion of Tim-3 led to reduction of CD8(+) T cell apoptosis. Administration of alpha-lactose, a molecule with a similar structure to galactin-9, reduced Tim-3 expression and liver injury in sepsis. Our results demonstrate that targeting Tim-3 to boost CD8(+) T cell immune response may offer an improved outcome in patients with sepsis.