The etiology of chronic rejection is unknown, although acute rejection, viral infection, and initial graft ischemia have been implicated. To test the effects of infections on the process of chronic rejection, we simulated bacterial infection by the administration of the endotoxin lipopolysaccharide (LPS), a potent activator of various cell types in an established rat model of chronic rejection. Lewis recipients of Fisher 344 kidneys were treated with a single dose of LPS or vehicle 8 weeks following transplantation and grafts were examined at various time points. In the chronically rejecting controls, leukocytic infiltration and the expression of cytokines peaked at 16 weeks. In LPS-treated hosts, leukocyte infiltration and cytokine expression peaked at 12 weeks. By 16 weeks, glomeruli in LPS-treated recipients had become far more sclerotic than those in controls, mimicking the changes observed in controls at 24 weeks. We conclude that infections may play an important role in the development of chronic rejection.