IgG anti-lymphocyte antibodies (ALA) reactive with resting lymphocytes were demonstrated in sera of patients with systemic lupus erythematosus (SLE) by immunofluorescence and flow cytometry and were shown (i) to bind T cells by non-Fc receptor-related mechanisms, (ii) to potentiate antibody-dependent cellular cytotoxicity (ADCC) of lymphocytes in vitro which correlated with binding to T cells, and (iii) to occur at a similar frequency in 29 SLE sera (56%) as IgM ALA (59%). IgG ALA levels in sera negatively correlated with absolute numbers of circulating lymphocytes in patients (r = -0.48, P less than 0.05), as did IgM ALA levels (r = -0.54, P less than 0.05); however, a stronger correlation resulted when levels of both ALA isotypes were considered together (r = -0.61, P less than 0.01). Different groups of SLE patients were distinguished with respect to relative serum content of IgM and IgG ALA and corresponding serum capacity to predominantly mediate ADCC, complement-dependent cytotoxicity (CDC), or both. No correlation existed between serum ADCC and CDC activities in vitro (r = 0.22). However, SLE patient lymphocyte counts negatively correlated with ADCC (r = -0.59, P less than 0.01) and to a lesser but still significant extent with CDC (r = -0.47, P less than 0.05). The latter results suggested that ADCC, induced by serum IgG ALA, was a mechanism of cytoloysis which occurred independently of CDC and which, like CDC, was significantly associated with lymphopenia in vivo.