MRL-lpr/lpr mice develop a severe autoimmune disease that resembles systemic lupus erythematosis in humans. The predominant immunological feature in these mice is the development of peripheral lymphadenopathy due to the expansion of an unusual T cell subset (TCR-alpha/beta +5CD3+4-8-B220+), which may be related to the onset of their autoimmunity. However, it is unknown whether such abnormal lymphocytes proliferate in the specific organs or not. We demonstrated in the present study that the number of liver nonparenchymal mononuclear cells (MNC) in the diseased MRL-lpr/lpr mice was 10 times greater than that of control MRL-+/+ mice. Moreover, the freshly isolated liver MNC of MRL-lpr/lpr mice vigorously proliferated in vitro and consisted of abnormal CD3+4-8- lymphocytes. Such in vitro proliferation was not observed in the MNC of other peripheral lymphoid organs. A potent natural cytotoxicity was also confined to the liver MNC in MRL-lpr/lpr mice. In vivo injection of [3H]TdR demonstrated that liver MNC incorporated [3H]TdR; such incorporation showed a peak on day 1, and the MNC-incorporated [3H]TdR appeared in the lymph nodes as late as day 5 after the injection. These results suggest that the liver is a possible site for the proliferation of abnormal lymphocytes, which may migrate thereafter into the peripheral organs in MRL-lpr/lpr mice.