To examine whether an abnormal zinc status contributes significantly to the impaired in vivo cell-mediated immunity of the genetically diabetic C57BL/KsJ db/db mouse, we measured specific cytotoxicity of spleen cells from db/db and heterozygous (db/m) and homozygous (m/m) control mice fed either zinc-deficient (2 mg/kg) or zinc-adequate (20 mg/kg) semipurified diets. Low serum and femur zinc concentrations were seen after 4 wk in all mice fed the zinc-deficient diet, but impaired cytotoxicity was not seen until later in control mice fed that diet. In contrast, db/db mice fed zinc-adequate diets had diminished spleen weights and markedly impaired cytotoxicity by 4 wk. These mice had normal serum and only mildly decreased femur zinc concentrations. We, therefore, found no evidence to suggest that the mildly altered zinc status of db/db mice fed zinc-adequate diets is a major factor contributing to their markedly impaired in vivo cell-mediated immunity.