Immunomodulation of cell-mediated immunity was studied in mice treated with either lithium chloride (LiCl), anti-CD8 monoclonal antibody or their combination. While 6-day LiCl treatment decreased the ability of their splenocytes to induce a local graft-versus-host reaction--anti-CD8 abolished this effect. The proliferative response of spleen cells from those three groups of mice to concanavalin A stimulation in vitro was significantly increased. The natural killer (NK) cell toxicity of the mice was decreased by over 43% after the 6-day LiCl treatment, but was x 2.5 higher then the control value after a longer 21-d treatment. These results indicate that the immunomodulatory capacity of lithium is dependent on the type of cell population studied, and on the schedule of administration.