Mice treated with purified anti-Lyt-2 monoclonal antibody (mAb) displayed a delayed ability to eliminate a primary Listeria monocytogenes infection from their spleens. Elimination of listeriae from the liver was unimpaired by anti-Lyt-2 mAb treatment. Treatment with anti-L3T4 mAb, alone or in combination with anti-Lyt-2 mAb, resulted in similar increases in the numbers of listeriae recovered from the spleens at 7 days after challenge. Listeria-infected mice that had been treated with anti-Lyt-2 mAb alone developed a strong delayed-type hypersensitivity (DTH) response, although it was significantly reduced as compared to control listeria-infected mice. In contrast, treatment with anti-L3T4 mAb severely impaired the development of DTH in listeria-infected mice. Treatment with anti-Lyt-2 mAb and anti-L3T4 mAb, singly or in combination, did not prevent mice from developing increased anti-listeria resistance if they were then immunized with a sublethal dose of L. monocytogenes. Treatment of mice with anti-Lyt-2 mAb or anti-L3T4 mAb before immunization, however, reduced the ability of their spleen cells to transfer anti-listeria resistance to recipient mice. These results indicate that Lyt-2+ cells make substantial contributions to the resistance of mice to primary L. monocytogenes infection, and to the ability of spleen cells from listeria-immunized mice to transfer resistance to naive recipients.