When syngeneic lymphocytes and mitomycin C-treated regenerating liver cells, prepared from partially hepatectomized mice, are cultured together, the in vitro DNA synthesis is activated (sMLHLR: syngeneic mixed hepatectomized-liver cell-lymphocyte culture). The Ia+ Kupffer cells play an important role as stimulators in the response, since the stimulating activity of regenerating liver cells is lost either by the pretreatment with anti-Ia monoclonal antibody plus complement or by the removing Kupffer cells from them. The lymphocytes are also activated in vivo during liver regeneration following partial hepatectomy. When lymphocytes, prepared from hepatectomized mice, are cultured with regenerating liver cells, the lymphocytes are stimulated to accelerate their DNA synthesis in a manner typical of the secondary immune responses (secondary sMLHLR). In primary sMLHLR, the responder cells are mainly Lyt-1+, whereas, in secondary sMLHLR, they are mainly Lyt-2+. The mechanism of changing the Lyt phenotype of major responder cells from Lyt-1 to Lyt-2 during sMLHLR is discussed.