Multiple periods of caloric restriction (or fasting)/refeeding in rodents have had inconsistent effects on mammary tumor (MT) development. In the present study, the consequence of intermittent caloric restriction/refeeding resulting in weight-cycling was evaluated using an oncogene-induced MT mouse model. Hybrid mouse MT virus-transforming growth factor alpha (MMTV-TGF-alpha)/Lep(+)Lep(ob) female mice were used. Ad libitum-fed mice (n = 30) were fed American Institute of Nutrition (AIN)-93M diet. Beginning at 10 weeks of age, weight-cycled mice (n = 30) were fed an AIN-93 modified diet (2-fold increase in protein, fat, vitamin, and mineral contents) at 50% of ad libitum for 3-week intervals followed by 3-week intervals of ad libitum feeding using AIN-93M diet. Pair-fed mice (n = 33), were fed a 2:1 mixture of AIN-93M:AIN-93 modified diets to match the caloric intake of weight-cycled mice for each 6-week age-matched caloric restriction/refeeding interval. Food intakes were determined daily and body weights weekly. Mice were euthanized when MTs exceeded 20 mm in length or at 80 weeks of age. Final body weights were similar, but cumulative food intake of ad libitum-fed mice was 21% greater than that of the other groups. Ad libitum-fed mice had a 77% MT incidence versus 3% for weight-cycled and 44% for pair-fed mice. MTs were detected earlier for ad libitum-fed mice, 64.1 weeks versus 73.5 weeks for pair-fed mice. The only MT in one weight-cycled mouse was excised at necropsy (80 weeks of age) and weighed only 0.063 g. Average MT weight for ad libitum-fed mice was 1.034 g and for pair-fed mice was 0.667 g. Intervals of caloric restriction/refeeding resulting in weight-cycling were protective against MT development in this mouse model. Future studies should address the application of this intervention to additional transgenic mice as well as other MT models.