We investigated whether stress increases tumorigenesis in male transgenic mice that overexpress the gene encoding human transforming growth factor alpha (TGF alpha). At the age of 10-15 months, these mice begin to develop spontaneous hepatocellular carcinomas at high incidence. The male TGF alpha mice were housed with their siblings (non-stressful environment), housed in social isolation, or housed with aggressive non-siblings (stressful environment). Some animals in each group were exposed once a week to a second stressor (swim stress), beginning at the age of 7 months. Housing with aggressive non-siblings increased neoplastic growth in the male TGF alpha mice: the incidence and multiplicity of liver tumors, and tumor burden were higher in these animals than in the sibling-housed mice. Among the isolated TGF alpha mice, only the tumor burden was increased, when compared with the sibling-housed TGF alpha mice. Swim stress significantly increased the incidence of liver tumors and tumor burden in the sibling-housed TGF alpha mice. Plasma levels of 17 beta-estradiol (E2) that are elevated in the TGF alpha mice, were modestly but significantly higher in the non-sibling housed transgenic mice than in the sibling-housed. Natural killer (NK) cell activity, reduced in these mice, was not affected by housing environment. These data suggest that stress promotes the growth of hepatocellular tumors in the male TGF alpha mice. Whether estrogens are involved in mediating this association remains to be determined.