The purpose of this study was to assess the effect of energy expenditure, via voluntary exercise, on growth of xenografts of human breast carcinomas in athymic nude mice. Sedentary and exercising athymic nude mice bearing subcutaneous grafts of MDA-MB231 human breast carcinomas were fed daily a purified high-fat diet at 10% less than ad libitum to ensure an equal quantity of diet (energy) consumption for each sedentary and exercising mouse. The sedentary and exercising mice were housed singly; the exercising mice had, in addition, access to an activity wheel (24 hrs/day). Growth of human breast carcinomas (carcinoma volumes) was evaluated during a five-week periods. Mean running activities of individual mice over the five-week period ranged from < 1 to 7.9 miles/day. Growth of the human breast carcinomas was significantly inversely correlated with the mean number of miles that each mouse ran per day (p < 0.018). Upon separation of these mice into two running groups, i.e., those that averaged 2.7-4.7 miles/day and those that averaged > 4.7 miles/day, carcinoma growth was 83% of sedentary controls in the former group (p = 0.305) and 59% of sedentary controls in the latter group (p = 0.039). These results provide evidence that energy expenditure, via voluntary use of an activity wheel, can reduce significantly the growth of human breast carcinomas maintained in athymic nude mice.