Adhesion of leukocytes to vascular endothelium is crucial for leukocyte migration into tissues. The contributions of L-selectin, P-selectin, and ICAM-1 to interactions between lymphocytes and endothelium was examined using allogeneic skin graft rejection as a model of cutaneous inflammation. L-selectin-deficient (L-selectin(-/-)) mice rejected both primary and secondary allogeneic (BALB/c) skin grafts significantly more slowly than L-selectin(+/+) littermates. Furthermore, skin graft rejection remained significantly delayed in L-selectin(-/-) mice, despite placement of grafts 7 days after i.p. immunization with allogeneic cells, when CTL responses in L-selectin(-/-) mice and L-selectin(+/+) littermates were confirmed to be equivalent. Indeed, specific CTL responses to BALB/c splenocytes were normal or elevated in L-selectin(-/-) mice following either skin grafts or immunization. However, the number of T lymphocytes within allogeneic grafts was lower in L-selectin(-/-) mice as compared with L-selectin(+/+) littermates. Therefore, delayed rejection of skin grafts by L-selectin(-/-) mice reflects impaired migration of effector cells into the graft rather than delayed or impaired generation of a CTL response. In contrast to L-selectin(-/-) mice, P-selectin-deficient and ICAM-1-deficient mice rejected allogeneic skin grafts normally. These findings delineate an important role for L-selectin in lymphocyte recruitment to cutaneous sites of inflammation.