Co-culture of natural killer (NK) cells and dendritic cells (DCs) results in their reciprocal co-activation, and an enhancement of lysis of tumor target cells. The receptor:ligand pairings mediating this enhancement are unknown. Therefore, we investigated whether interactions of CD161, on NK cells, with Clrs, on DCs, might have a role in this effect. Blocking expression of CD161B using siRNA resulted in a reduction in enhanced lytic activity following NK:DC co-culture. Conversely, blocking expression of CD161F with siRNA had no effect on enhanced lytic function following NK:DC co-culture. Blocking expression of ClrB/Ocil, a ligand for CD161B, resulted in a reduced level of enhanced lytic function following NK:DC co-culture. This is the first report of NK receptors responsible for interaction with DCs having a role in mediating enhanced lytic function following NK:DC interactions.