Trichloroethylene (TCE) is a widespread environmental pollutant associated with immunotoxicity and autoimmune disease. Previous studies showed that mice exposed from gestation through early life demonstrated CD4+ T cell alterations and autoimmune hepatitis. Determining the role of one environmental risk factor for any disease is complicated by the presence of other stressors. Based on its known effects, we hypothesized that developmental overnutrition in the form of a moderately high-fat diet (HFD) consisting of 40% kcal fat would exacerbate the immunotoxicity and autoimmune-promoting effects of low-level (<10 μg/kg/day) TCE in autoimmune-prone MRL+/+ mice over either stressor alone. When female offspring were evaluated at 27 weeks of age we found that a continuous exposure beginning at 4 weeks preconception in the dams until 10 weeks of age in offspring that TCE and HFD promoted unique effects that were often antagonistic. For a number of adiposity endpoints, TCE significantly reversed the expected effects of HFD on expression of genes involved in fatty acid synthesis/insulin resistance, as well as mean pathology scores of steatosis. Although none of the animals developed pathological signs of autoimmune hepatitis, the mice generated unique patterns of antiliver antibodies detected by western blotting attributable to TCE exposure. A majority of cytokines in liver, gut, and splenic CD4+ T cells were significantly altered by TCE, but not HFD. Levels of bacterial populations in the intestinal ileum were also altered by TCE exposure rather than HFD. Thus, in contrast to our expectations this coexposure did not promote synergistic effects.