The effect of social confrontation on the susceptibility to metastatic development was studied in rats. An intruder male Fischer 344 (F344) was introduced to a male-female Long-Evans pair and the behavior was recorded during the first 30 min of a 7-h confrontation session. Mammary tumor cells (MADB106), syngeneic to the inbred F344 rat, were injected i.v. to the intruder 1 h after the beginning of the confrontation session, and the lung retention of tumor cells was determined 24 h later. In this tumor model, metastases develop only in the lungs. Retention of tumor cells and the consequent development of lung colonies are known to be highly controlled by the activity levels of natural killer cells during the first 24 h after tumor inoculation but not later. Twenty of the 21 intruders were attacked by resident males and 19 displayed submissive behavior. A significant increase in lung tumor retention was evident in intruders compared to both control groups: home cage and new environment. The magnitude of this increase was higher in intruders that frequently displayed submissive behavior (indicating social defeat). Pretreatment with the beta-adrenergic antagonist, butoxamine, reduced the effects of social confrontation by approximately 50%, and adrenal demedullation almost abolished it without significantly affecting the social interaction. These findings suggest that the nature of intruder-resident interaction, rather than being subdominant or exposure to an unfamiliar environment, has a marked influence on the intruder's susceptibility to metastatic development. These effects of social confrontation seem to be mediated by adrenergic mechanisms, possibly via adrenergic influence on NK function and distribution.