The effects that divalent metals have on nickel‐induced suppression of natural killer (NK) cell activity were studied in mice. Male CBA/J mice were given a single intramuscular injection of metal salt on a body weight basis. The metal doses used were the following: nickel chloride, 4.5–36 μg/g; manganese chloride, 20–80 μg/g; magnesium acetate, 50–200 μg/g; zinc acetate, 2–8 μg/g; or calcium acetate, 12.5–50 μg/g. Twenty‐four hours after metal injection, splenic NK cell activity was assessed using a51Cr‐release assay. Ni significantly (p< 0.01) suppressed NK activity, while Mn significantly (p< 0.01) enhanced NK activity. No alteration in NK activity was observed in mice injected with Mg, Ca, or Zn. Since these divalent metals have been shown to have antagonistic effects on Ni‐induced carcinogenicity and toxicity, they were used in combination with Ni to determine if such antagonisms exist for NK cell activity. The injection of Ni and Mn in combination at a single site resulted in the enhancement of NK activity, although this enhancement was at a level below that observed following the injection of Mn alone. Injection of Mg, Zn, or Ca in combination with Ni did not affect NK activity compared to saline controls. In contrast, the injection of Ni in one thigh followed immediately by Mn, Mg, Ca, or Zn into the other thigh resulted in significant suppression of NK activity for all metals compared with saline controls. An interesting finding was that the injection of Ni followed immediately by Mn into the opposite thigh resulted in even greater reductions in NK activity than Ni alone. Suppression of NK activity by Ni and Mn injected at separate sites was not seen when Mn injection preceded Ni injection by 1 h. These data indicate that both the divalent metal and the timing of its injection relative to Ni injection are critical for altering Ni‐induced suppression of NK cell activity.