The effect of radioactive lipid A, obtained from Escherichia coli, on the kidney of adult dogs and puppies was investigated. Injection of lipid A into the temporarily occluded renal pelvis of adult dogs caused abacterial interstitial nephritis in all animals tested. The intensity and duration of the kidney response coorelated well with the lipid A dose administered. Lipid A was demonstrated autoradiographically in the renal cortex, extra- and intracellularly. Radioactivity was still present after 10 weeks in 16 of 20 examined dogs. In the remaining four dogs the interstitial nephritis had subsided. Thirteen of 14 puppies in which the immunologic defense mechanisms had not yet developed showed no histologic reaction in the kidney after the same procedure as in the adult dogs. Lipid A appeared in the renal parenchyma through the blood stream rather than through the retrograde route. Lipid A antibody titers could be detected only in adult dogs, never in puppies. Lipid A apparently provoked an immunologic process in the kidney damaged by the operative manipulations, thus resulting in an abacterial interstitial nephritis. The possibility that chronic abacterial pyelonephritis can be induced clinically through lipid A and thus may have a pathogenesis similar to abacterial interstitial nephritis is discussed.