Normal human peripheral blood polymorphonuclear leukocytes (PMNs) and cells from a human acute promyelocytic leukemia line (HL-60) were tested for cytotoxic potential against two human glioma and one normal fibroblast line. Both the PMNs and HL-60 exhibited significant cytotoxicity against the tumor targets while sparing the normal fibroblasts. However, the two glioma cell lines were not equally susceptible to the effector cells. Addition of low levels of purified human lymphoblastoid interferon alpha (IFN) during the assay period significantly enhanced the tumoricidal effect against one of the glioma targets. HL-60 cells, partially differentiated to myelocytes and metamyelocytes by incubation with dimethylsulfoxide (DMSO), expressed reduced levels of cytotoxicity; IFN added during the assay was able to restore the cytotoxic activity against both glioma cell lines. Undifferentiated HL-60 cells were also able to lyse K562 targets in a six hour 51Cr release assay; this activity was also significantly enhanced by IFN. Separate incubation of both effectors and targets proved that the enhancement of cytotoxic activity demonstrated was due to an effect on the HL-60 effector cells. In contrast, the lysis of HSB-2, another NK sensitive target cell, was not enhanced by the addition of IFN to a mixture of HSB-2 and HL-60 cells. Pretreatment of effector and target cells separately with IFN demonstrated a dual effect: IFN both protected HSB-2 targets from lysis by the HL-60 effectors and induced significantly greater cytotoxicity by HL-60 cells.