Studies were undertaken to determine whether leukemia and lymphoma cells would be lysed by autologous and allogeneic interferon (IFN) activated peripheral blood mononuclear cells (PBMC). PBMC from healthy donors and from patients were cultured with and without 500 U of highly purified human fibroblast IFN/ml for 24 hr, and then their cytotoxic activity was assayed by a 5-hr 51Cr-release test. Of primary tumor cells isolated from patients, the cells of 5 of 15 patients with acute nonlymphocytic leukemia (ANLL), 5 of 9 patients with acute lymphocytic leukemia (ALL), 2 of 3 patients with chronic phase chronic myelogenous leukemia (CML), 2 of 3 patients with blastic phase CML, 1 patient with hairy cell leukemia, and 6 patients with diffuse non-Hodgkin's lymphoma were sensitive to IFN-activated PBMC of healthy donors, whereas the cells of 3 of the ANLL patients, 2 of the ALL patients, and 3 of the lymphoma patients were sensitive to unstimulated PBMC. Of the ANLL cells tested, myeloblasts, promyelocytes, and monoblasts were sensitive to either unstimulated or IFN-activated PBMC. Compared with the ANLL cells, the lymphoma cells were statistically significantly sensitive to activated effector cells (p less than 0.025). On the basis of the unlabeled target competition test and the recovery of cytotoxic cells within the fractions enriched in natural killer (NK) cells, NK cells appeared to mediate the above unstimulated and IFN-boosted cytotoxicity. In experiments using autologous effector-target cells from 11 patients, the addition of 500 U of IFN/ml enhanced the lytic activity of PBMC against autologous lymphoma cells in 1 patient, and higher concentrations of IFN, i.e., 2500 or 3500 U/ml, enhanced their cytotoxic activity against autologous leukemia or lymphoma cells in 4 of 8 patients. These data indicate that IFN-activated allogeneic PBMC are able to lyse both myeloid and lymphoid tumor cells, whereas higher concentrations of IFN are required to enhance lytic activity against autologous tumor cells.