The effects of nickel chloride on the cellular and humoral immune responses of mice were studied. A single intramuscular injection of nickel chloride (18.3 mg/kg) caused a significant involution of the thymus within 2 days following treatment. Significant reductions in the in vitro mitogen-stimulated response of lymphocytes from nickel chloride-treated mice (24 hr following a single injection of 18.3 or 36.6 mg/kg) were observed for the T-cell mitogens phytohemagglutinin (PHA) and concanavalin A (Con A), and the B- and T-cell mitogen pokeweed mitogen (PWM) but not the B-cell mitogen lipopolysaccharide (LPS). Theta-positive but not Ig-positive spleen cells were significantly reduced in nickel-treated mice compared with controls. Significant suppression of the primary antibody response to the T-cell dependent antigen sheep red blood cells was observed following a single injection of 18.3 mg/kg NiCl2. Natural killer (NK) cell activity was significantly suppressed following a single injection of 18.3 mg/kg NiCl2. The administration of NiCl2 (18.3 mg/kg) also decreased the amount of endotoxin required to kill 50% of treated mice, although this was not statistically significant. In all cases the immunosuppressive effects of NiCl2 were found to be transient with responses returning to normal within a few days. No alteration in the response of mice immunized with the T-cell independent antigen polyvinylpyrrolidone was observed following treatment with nickel. Furthermore, the phagocytic capacity of resident peritoneal macrophages from nickel-treated mice was not significantly different from saline-injected mice. The results indicate that NiCl2 predominantly affects T-cell mediated immune responses and natural killer cells.