Six-week-old C57B1/6 female mice were fed a normal (24% protein) or an isocaloric but protein-deficient (4% protein) diet. At different time periods after the initiation of diets, basal natural killer (NK) activity, interleukin-2 (IL-2) and concanavalin-A (Con-A)-induced cytotoxic activity, Con-A-induced IL-2 production and levels of allospecific cytotoxic T cell activity generated in a mixed lymphocyte culture (MLC), were studied in spleen cells derived from control and protein deficient (PD) mice. Results indicated that (a) levels of spleen NK activity increased initially in PD mice, but after 7 weeks on PD diet declined to normal and subnormal levels, (b) IL-2 generation in response to Con-A as well as IL-2 activation of NK activity were comparable in spleen cells of control and PD mice at all time points tested, (c) Con-A-induced cytotoxic activity was significantly greater in spleen cells from PD mice, the difference being greater at higher doses of Con-A, and (d) generation of alloimmune cytotoxic T cells in a MLC reaction was normal in PD mouse spleen cells until 4 weeks after the beginning of PD diet, but declined markedly thereafter. Relevance of these observations to other related findings in protein calorie malnutrition are discussed.