Lead (Pb) is a highly toxic metal that can induce oxidative stress and affect the immune system by modifying the expression of immunomodulator-related genes. The aim of the present study was to investigate the association between Pb exposure and the transcriptional profiles of some cytokines, as well as the relationship between Pb exposure and changes in oxidative stress biomarkers observed in the spleen of wild ungulates exposed to mining pollution. Red deer and wild boar from the mining area studied had higher spleen, liver, and bone Pb levels than controls, indicating a chronic exposure to Pb pollution. Such exposure caused a depletion of spleen glutathione levels in both species and disrupted the activity of antioxidant enzymes, suggesting the generation of oxidative stress conditions. Deer from the mining area also showed an induced T-helper (Th)–dependent immune response toward the Th2 pathway, whereas boar from the mining area showed a cytokine profile suggesting an inclination of the immune response toward the Th1 pathway. These results indicate that environmental exposure to Pb may alter immune responses in wild ungulates exposed to mining pollution. However, evidence of direct relationships between Pb-mediated oxidative stress and the changes detected in immune responses were not found. Further research is needed to evaluate the immunotoxic potential of Pb pollution, also considering the prevalence of chronic infectious diseases in wildlife in environments affected by mining activities. ; J. Rodríguez-Estival had a Junta de Comunidades de Castilla-La Mancha predoctoral grant. The Department of Education and Science of the Junta de Comunidades de Castilla-La Mancha funded this study (projects PCC-05-004-2 and PCI08-0096-1295). ; Peer reviewed