Previously we demonstrated that some osteosarcoma cell lines varied greatly in their susceptibility to natural killer (NK) cell lysis in vitro. The expression of CD54 and CD58 adhesion molecules on their surface appeared to influence their vulnerability, and the tumour necrosis factor-alpha (TNF-alpha)-induced positive modulation of CD54 increased osteosarcoma susceptibility in vitro. This study investigated whether peripheral blood mononuclear cells from normal healthy donors could be activated by interleukin (IL)-12 and IL-2, separately or in combination, to lyse osteosarcoma cell lines in vitro, as evaluated by using a microcytotoxicity test. In addition, we analysed (by flow cytometry) whether this function correlated with modifications of the CD2, CD11a, CD11b and CD18 molecules, which are involved in the adhesion of effector cells to the counter-receptors (CD54 and CD58) on osteosarcomas. This study demonstrates that incubation with IL-12 and/or IL-2 triggered NK cell cytolytic activity against osteosarcoma targets and that cytolytic activity was enhanced to a greater extent when lymphocytes were incubated simultaneously with a combination of IL-12 and IL-2. The density of CD18 and CD2 molecules involved in NK adhesion was also up-modulated following cytokine incubation. These changes in the density of adhesion molecules can be involved in the increased lytic activity of effector lymphocytes and in the modification of their binding capacity to osteosarcoma target cells.