Cultured cell lines derived from malignant Epstein-Barr virus (EBV)-negative B cells, and representative of the more common types of naturally occurring non-Hodgkin lymphomas and related leukemias, were found to be sensitive to lysis by human natural killer (NK) cells. The observed lysis of such cell lines was mediated by a population of interferon-augmentable, FcR-positive, non-adherent lymphoid cells, which were also able to kill the "standard" NK targets K562 and Molt-4. When the NK susceptibility of the neoplastic, EBV-negative B cells was compared to that of diploid, EBV-carrying, non-neoplastic B lymphoblastoid cell lines (BLCLs) and of the "standard" NK target K562, several distinct patterns were observed. The killing of the neoplastic B cell lines was significantly less than that of K562, but significantly greater than that of the EBV-derived BLCLs of non-neoplastic origin. An additional finding was a similar NK susceptibility profile for the neoplastic, true histiocytic cell line U-937 (i.e., K562 greater than U937 greater than BLCLs). Furthermore, all cell lines, with the exception of the BLCLs, could effectively compete for the observed killing in cold target inhibition assays. The implications of these findings are discussed in relation to both neoplastic and non-neoplastic targets of NK lysis.