Cloned lymphocytic choriomeningitis virus (LCMV)-specific cytotoxic T lymphocyte (CTL) lines were prepared from spleens of 129/J (H-2b) mice immunized 7-9 months earlier with LCMV (UBC strain), or of C57BL/10J (H-2b) mice immunized 4 to 5 weeks earlier with LCMV (Armstrong strain). One uncloned and 3 cloned cytotoxic T cell lines were assessed for their respective abilities to produce, or protect against, fatal disease upon transfer to appropriate recipients or to induce specific footpad-swelling reaction. The effects of all lines were essentially identical. In recipient mice acutely infected with LCMV and immunosuppressed either by irradiation (750-990 rds) or treatment with cyclophosphamide, cloned T cells administered intracerebrally (i.c.) caused a convulsive disease and death within 1-4 days. No disease was produced when the same CTL were transferred to uninfected recipients or when they had been frozen and thawed prior to transfer to infected recipients. When admixed with 500 plaque-forming units of LCMV and transferred i.c. to immunocompetent H-2b mice, the T cell clones prevented overt disease. Allogeneic (H-2k) recipients of this same admixture all developed typical LCM disease as did H-2b recipients of the admixture after T cells had been frozen and thawed. Inoculation of cloned CTL into preinfected footpads induced a specific footpad-swelling reaction, which reached maximum levels after about 36 h. Irradiated and infected recipients of cloned LCMV-specific T cells showed the footpad-swelling reaction only when they had been reconstituted with bone marrow cells. In contrast, cloned T cells induced LCM disease in i.c. infected and irradiated mice independent of bone marrow reconstitution. These findings indicate that both fatal LCMV-induced neurologic disease and protection against it are mediated directly by virus-specific CTL.