Cytotoxic T lymphocytes (CTL) recognize and lyse target cells through the interaction of the T-cell receptor complex with the class I or class II major histocompatibility complex (MHC). The production of class I-restricted CTL has been shown to be critical to the elimination of specific pathogens including Listeria monocytogenes. However, the function of class II-restricted CTL in the clearance of intracellular pathogens is poorly understood. H-2b beta 2-microglobulin-deficient mice (beta 2M-/-) are not able to produce CD8+ CTL in response to infection with L. monocytogenes. We used this model to evaluate the efficacy of class II-restricted CTL, in the absence of a class I-restricted response, during a primary infection with L. monocytogenes. We demonstrate that, despite their effectiveness in adoptive transfer of protection, Listeria-specific CD4+ class II-restricted cytotoxic lymphocytes are ineffective in decreasing titres of L. monocytogenes in the spleen was found established infection. In beta 2M-/- mice, persistence of L. monocytogenes in the spleen was found preferentially in class II-negative cells. Surprisingly, class I-restricted CTL from C57BL/6 mice were capable of decreasing bacterial titres during an established infection even in the absence of detectable class I on the surface of cells from beta 2M-/- mice. These data strongly suggest that, in the absence of a class I-restricted response, pathogens that elicit a class II-restricted cytotoxic response may escape prompt eradication by the immune system.