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On exposure to stressors, energy is diverted from non-urgent functions towards those important for immediate survival. The degree and nature of reallocation may be affected by the evolutionary history of the animal. The eastern fence lizard (Sceloporus undulatus) coexists in parts of its range with invasive fire ants (Solenopsis invicta), which attack and wound lizards and elevate stress-relevant hormones (corticosterone), whereas other populations have never been exposed to fire ants. We examined how a history of fire ant invasion affected the immune response in female lizards after exposure to exogenous corticosterone (mimicking exposure to a stressor) during gestation (dosing regimens differed among corticosterone-exposed lizards owing to the constraints of the original studies, but we found no evidence that this affected the outcome of the present study). A history of exposure to predatory stressors (fire ants) and corticosterone treatment affected cell-mediated immunity. Lizards from fire ant-invaded sites had a reduced immune response compared with those from uninvaded sites. Corticosterone treatment had no effect on the immune response of lizards from invaded sites but reduced the immune response of lizards from uninvaded sites. This suggests that an evolutionary history of exposure to wounding alters the immune response to corticosterone. Future work on how the immune system responds to environmental threats will be informative for the prediction and management of these threats.