Two out of 25 monoclonal anti‐DNA autoantibodies that were produced by human‐human hybridoma were found to have lymphocytotoxic activity. The antibodies reacted with normal B and T lymphocytes at cold (4°C) as well as at warm (37°C) temperatures. The lymphocytotoxic activity of the monoclonal anti‐DNA antibodies could be inhibited by prior incubation of the antibodies with either polynucleotides, e.g. poly (I), poly(dT) or anti‐idiotypic antibodies, that had been raised against a dominant anti‐DNA antibody. The cross‐reactivity between nuclear material and lymphocyte membrane raises the question whether these apparently diverse materials have a shared epitope. The cross‐reactivity between anti‐DNA antibodies and lymphocyte membrane may account in part for the lymphopenia observed in systemic lupus erythematosus patients.