The ability of peripheral blood lymphocytes to respond in vitro to phytohemagglutinin (PHA) and to allogeneic cells in mixed leukocyte reaction (MLC) was studied in 85 patients with cancer and in 50 healthy controls. The effect produced by sera from cancer patients on in vitro lymphocyte blastogenesis was tested on autologous cells and on homologous cells from a constant panel of 10 normal volunteers. Patients with cancer showed a distinct deficiency of cellular immune responsiveness reflected in a stage-related impairment of PHA and MLC reactivity. This deficiency seems at least partially attributable to the presence of lymphocyte depressive factors in cancer sera, since such sera reduced the reactivity of both autologous and normal homologous lymphocytes to a level that was significantly lower than that found in the presence of pooled normal serum. The inhibitory activity of cancer sera was directly related to the extent of the neoplasia.