We have studied the autologous mixed lymphocyte reaction (AMLR) in 3 strains of mice with autoimmune disease. T cell proliferation to autologous non-T cells occurs in young mice of these 3 strains (as it does in normal mice) but is absent or greatly reduced in older mice of strains with autoimmune disease. Reciprocal mixing experiments revealed that the defect in the AMLR of the older mice resides in the responder T cell population. Further analysis of the cells participating in the AMLR of young mice of the B/W F1 strain revealed that: 1) a Thy 1- and Ly1-positive responder cell was necessary at the start of the culture to initiate the AMLR; 2) the cells present after 5 days of culture contained very few, if any, Ly123 cells in the B/W F1 strain compared with the normal C57BL/6 strain; and 3) the stimulating cell appear to be a macrophage, and an Ia-bearing cell must be present for the reaction to occur.