L-deprenyl, a monoamine oxidase-B inhibitor, has been shown to reverse the age-related decline in sympathetic noradrenergic innervation and immune function in old rats and enhance T cell and NK cell activity in tumor-bearing rats. The objective of the present study was to examine whether deprenyl treatment of old female rats with mammary tumors could augment sympathetic nervous system and immune responses to inhibit the tumor growth. Female Sprague-Dawley rats with spontaneous mammary tumors were administered 0, 2.5 mg, or 5.0 mg/kg body weight (BW)/day deprenyl for i.p. 9 weeks. Tumor diameter, tumor number and body weight were measured throughout the treatment period. At the end of the treatment period, norepinephrine (NE) concentration, interferon-gamma production (IFN-gamma), Con A-induced T lymphocyte proliferation, and percentage of T and B lymphocytes and natural killer cells were measured in the spleen, and the concentrations of monoamines were measured in the medial basal hypothalamus. Relative to saline-treated controls, treatment with deprenyl reduced tumor growth, increased NE concentration, IFN-gamma production and percentage of the CD8+ T lymphocytes in the spleen. In the medial basal hypothalamus, deprenyl treatment increased the concentrations of catecholamines and indoleamine. These results suggest that the anti-tumor effects of deprenyl on spontaneous rat mammary tumors may be achieved via neural-immune signaling in the spleen and medial basal hypothalamus.