We showed previously that a diet rich in linoleic acid (LA), an omega-6 fatty acid, stimulates the growth and metastasis of human breast cancer cells in athymic nude mice. In contrast, diets supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), omega-3 fatty acids, exert suppressive effects. We have now assessed EPA and DHA as adjuvant nutritional therapy in the nude mouse model and compared the responses when the intervention was commenced 1 week before ("neoadjuvant") or immediately after ("postoperative adjuvant") surgical excision of the primary tumor. Female nude mice received a high-fat, 8% LA diet beginning 7 days before 10(6) MDA-MB-435 human breast cancer cells were injected into a thoracic mammary fat pad. As the tumor surface areas approached 0. 7 cm2, the mice were assigned to either continue on the LA-rich diet or to commence one containing 8, 4, or 2% EPA or DHA. Seven days later, the mammary fat pad tumors were excised; the mice still consuming the 8% LA diet were then allocated sequentially to either continue this diet or commence one of the six postexcision omega-3 fatty acid dietary interventions. Eight weeks later, the mice were necropsied and evaluated for local recurrence and lung metastases. Although there were no differences in the incidence of local recurrence between groups, EPA and DHA both inhibited the development of lung metastases. When the dietary interventions were commenced 7 days before surgery, the severity of lung metastasis was reduced by the two omega-3 fatty acids in a dose-dependent manner; at all three levels, the suppressive effects were statistically significant (P < 0.05). Postexcision EPA treatment produced small, statistically insignificant effects, but lung involvement was reduced significantly by feeding DHA at the 2 and 4% levels (P < 0. 05). Overall, these results suggest that omega-3 fatty acids may have a place as adjuvant nutritional therapy in breast cancer and particularly as part of a neoadjuvant regimen.