The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2x protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.