Resistance to murine toxoplasmic encephalitis has been precisely and definitively mapped to the L d class I gene. Consistent with this, CD8+ T cells can adoptively transfer resistance to toxoplasmic encephalitis. However, cytotoxic CD8+ T cells, capable of killing class I-matched, infected target cells, are generated during the course of Toxoplasma gondii infection even in mice lacking the L d gene. L d-restricted killing could not be demonstrated, and the functional correlate of the L d gene has therefore remained elusive. Herein, L d-restricted killing of T. gondii-infected target cells is demonstrated for the first time. L d-restricted killing is critically dependent on the strain of T. gondii and is observed with all the derivatives of type II strains tested, but not with a type I strain. These results have important implications for vaccine development.