While tumor necrosis factor (TNF)-α is an important mediator of renal ischemia-reperfusion (I/R) injury, its role in contralateral renal injury after isolated renal ischemia remains unknown. We therefore investigated the effect of isolated left renal ischemia on the nonischemic contralateral kidney. To study this, male Sprague-Dawley rats were anesthetized and exposed to varying degrees of left renal I/R injury. Both kidneys were subsequently harvested, serum samples were obtained, and TNF-α protein expression (ELISA), TNF-α mRNA content (RT-PCR), TNF-α immunolocalization, and neutrophil infiltration (myeloperoxidase assay) were determined. The effect of TNF-α on neutrophil infiltration was assessed by neutralizing TNF-α with TNF binding protein (TNF-BP) before left renal I/R injury. TNF-α protein expression, TNF-α mRNA induction, and neutrophil infiltration increased significantly in both kidneys after unilateral renal I/R injury. Furthermore, the administration of TNF-BP before unilateral renal I/R substantially reduced the degree of neutrophil infiltration bilaterally. These results constitute the initial demonstration that unilateral renal I/R induces bilateral TNF-α production and neutrophil infiltration through a TNF-α-dependent mechanism.