In a study of renal allografts with acute rejection primarily or exclusively of the cellular type, extratubular Tamm-Horsfall protein was identified in 63.6% of the specimens, representing 76.1% of the patients whose tissues were examined. There was no evidence of extrarenal obstruction in any patient. This high incidence has not been previously reported. A pattern of development of this phenomenon was determined using combined light and electron microscopies and specific anti-Tamm-Horsfall antiserum. Interstitial lymphocytes and monocytes infiltrated into the walls of tubules causing disruptions of basement membranes, thereby creating free communications between lumina and interstitium. In distal tubules with casts, the matrices extended into the interstitium where they were admixed with leukocytes and few erythrocytes. In a small number of specimens, polyps of Tamm-Horsfall protein were identified in veins or interstitial capillaries. Extratubular Tamm-Horsfall protein was not associated with diminished graft survival. These findings delineate, in detail, one of several mechanisms of escape of Tamm-Horsfall protein from tubules into the interstitium; they may be applicable for the genesis of this abnormality in other forms of acute interstitial nephritis.