The purpose of this study was to investigate the mechanism by which underfeeding induces regression of carcinogen-induced mammary tumors in the rat and to determine if tumor regression in underfed rats could be prevented on a chronic basis by maintaining elevated circulating levels of estrogen and/or prolactin (PRL) by treatment with estradiol benzoate (EB) and a dopamine receptor blocker, haloperidol (HAL). Female rats with 7,12-dimethylbenzanthracene-induced mammary tumors were fed ad libitum (full-fed), half-fed (HF), or half-fed and treated wtih EB (HF+EB), HAL (HF+HAL), or both (HF+EB+HAL) for 15 weeks. Tumor diameter, tumor number, and body weight were determined each week. At the end of the experiment, hypothalamic concentrations of catecholamines, indoleamines, and their metabolites were determined by high performance liquid chromatography. Tumor diameter, tumor number, and body weight increased progressively in the full-fed rats, but decreased significantly in the HF rats. Treatment of HF rats with EB, HAL, or both prevented tumor regression, but had no effect on body weight, which declined continuously. In the HF rats, there was an increase in the concentration of dopamine and a decrease in the concentration of serotonin in the hypothalamus, whereas treatment with HAL reversed these effects. EB had no effect on neurotransmitter concentrations in the HF rats, but treatment of HF+EB animals with HAL decreased the dopamine concentration. The changes in dopamine and serotonin observed in HF rats are known to inhibit PRL secretion, whereas HAL, which blocked these changes, is a well established stimulator of PRL secretion. Since the mammary tumors are dependent on PRL for development and growth, it is probable that the regression of these tumors in the HF rats was ultimately due to a decrease in PRL secretion, and the prevention of this regression in HF+HAL rats was ultimately due to an increase in PRL secretion. EB, a potent PRL stimulator, probably blocked tumor regression in HF+EB rats by increasing PRL secretion by a direct effect on the pituitary.