Interactions between the nervous system and the immune system have been recognized as important regulatory processes in determining the activity of the immune response. We have previously shown that rats, which differ in the reactivity of the dopaminergic system (APO-SUS and APO-UNSUS rats), also differ in experimental metastasis formation and in susceptibility to autoimmunity. APO-SUS rats have a high response to administration of apomorphine and can be characterized as hyperdopaminergic, whereas their APO-UNSUS counterparts show low susceptibility to apomorphine and have a hypodopaminergic phenotype. In this study we investigated whether the decreased experimental metastasis formation of APO-SUS rats compared to APO-UNSUS rats is associated with higher natural killer cell activity in APO-SUS rats. Surprisingly, splenic NK cell activity of hyperdopaminergic APO-SUS female as well as male rats is significantly lower than NK cell activity of their hypodopaminergic APO-UNSUS counterparts. The reduced splenic NK activity of female APO-SUS rats is associated with lower percentages of NK cells in the spleen cell population. In contrast, male APO-SUS and APO-UNSUS rats show similar numbers of NK cells in the spleen. There was no difference in plasma dopamine levels between APO-SUS and APO-UNSUS rats and i.p. treatment of rats with the dopaminergic agonist quinpirole did not alter NK cell activity. In conclusion, our data demonstrate that differences in the reactivity of the dopaminergic system are associated with differences in splenic NK cell activity. Moreover, our data demonstrate that in this model lower splenic NK cell activity is not related to increased experimental lung metastasis formation.