This study investigated the numbers of large granular lymphocytes (LGL) and their relationship to natural killer (NK) function, as assessed by their capacity to lyse the human tumor target, K562. Peripheral blood mononuclear cells from 42 normal controls and from 171 patients suffering from various nonmalignant or malignant diseases were evaluated. Also studied were samples from a patient undergoing autologous bone marrow reconstitution following total body irradiation. Results suggested the existence of a close relationship between the numbers of LGL and the capacity to lyse K562 targets, further supporting the view that LGL are crucial effector cells mediating NK lysis. In certain diseases, such as malignant states, functional capacity was not simply determined by the numbers of LGL. Here preferential reduction of the capacity to lyse K562 targets was observed, indicating that additional limiting factors are involved in the determination of the cytotoxic potential. Based on the relationship between LGL and natural immune functions, as well as on the identification of leukemias affecting this cell type, we would recommend their evaluation on a large scale clinical basis.