Background: Brain death (BD) is characterized by a complex inflammatory response, resulting in dysfunction of potentially transplantable organs. This process is modulated by cytokines, which amplify graft immunogenicity. We have investigated the inflammatory response in an animal model of BD and analyzed the effects of thalidomide, a drug with powerful immunomodulatory properties. Methods: BD was induced in male Lewis rats. We studied three groups: Control (sham-operated rats) (n = 6), BD (rats subjected to brain death) (n = 6) and BD + Thalid (BD rats treated with one dose of thalidomide (200 mg/ Kg), administered by gavage) (n = 6). Six hours after BD, serum levels of urea and creatinine, as well as systemic and renal tissue protein levels of TNF-alpha and IL-6, were analyzed. We also determined the mRNA expression of ET-1, and macrophage infiltration by immunohistochemistry. Results: BD induced a striking inflammatory status, demonstrated by a significant increase of plasma cytokines: TNF-alpha (2.8 +/- 4.3 pg/mL [BD] vs. 9.4 +/- 2.8 pg/mL [Control]), and IL-6 (6219.5 +/- 1380.6 pg/mL [BD] vs. 1854.7 +/- 822.6 pg/mL [Control]), and in the renal tissue: TNF-alpha (2.5 +/- 0.3 relative expression [BD] vs. 1.0 +/- 0.4 relative expression [Control]; p < 0.05), and IL-6 (4.0 +/- 0.4 relative expression [BD] vs. 1.0 +/- 0.3 relative expression [Control]; p < 0.05). Moreover, BD increased macrophages infiltration (2.47 +/- 0.07 cells/field [BD] vs. 1.20 +/- 0.05 cells/field [Control]; p < 0.05), and ET-1 gene expression (2.5 +/- 0.3 relative expression [BD] vs. 1.0 +/- 0.2 relative expression [Control]; p < 0.05). In addition, we have observed deterioration in renal function, characterized by an increase of urea (194.7 +/- 25.0 mg/dL [BD] vs. 108.0 +/- 14.2 mg/dL [Control]; p < 0.05) and creatinine (1.4 +/- 0.04 mg/dL [BD] vs. 1.0 +/- 0.07 mg/dL [Control]; p < 0.05) levels. Thalidomide administration significantly reduced plasma cytokines: TNF-alpha (5.1 +/- 1.4 pg/mL [BD + Thalid] vs. BD; p < 0.05), and IL-6 (1056.5 +/- 488.3 pg/mL [BD + Thalid] vs. BD; p < 0.05), as well as in the renal tissue: TNF-alpha (1.5 +/- 0.2 relative expression [BD + Thalid] vs. BD; p < 0.05), and IL-6 (2.1 +/- 0.3 relative expression [BD + Thalid] vs. BD; p < 0.05). Thalidomide treatment also induced a significant decrease in the expression of ET-1 (1.4 +/- 0.3 relative expression [BD + Thalid] vs. BD; p < 0.05), and macrophages infiltration (1.17 +/- 0.06 cells/field [BD + Thalid] vs. BD; p < 0.05). Also thalidomide prevented kidney function failure by reduced urea (148.3 +/- 4.4 mg/dL [BD + Thalid] vs. BD; p < 0.05), and creatinine (1.1 +/- 0.14 mg/dL [BD + Thalid] vs. BD; p < 0.05). Conclusions: The immunomodulatory properties of thalidomide were effective in decreasing systemic and local immunologic response, leading to diminished renal damage, as reflected in the decrease of urea and creatinine levels. These results suggest that use of thalidomide may represent a potential strategy for treating in BD kidney organ donors.