Tubulointerstitial nephritis developed in 25 of 34 (74%) rabbits challenged intravenously for 2-20 weeks with adjuvant and endotoxin free homologous Tamm-Horsfall protein (THP). Lesions were characterized by focal mononuclear cellular infiltrates and microscopic scarring localized to distal nephron segments identified as thick ascending limb of the loop of Henle. Interstitial deposits of THP were found in the kidneys of more severely affected rabbits and metabolic studies demonstrated transient polyuria and tubular dysfunction. Elevations in serum IgG antibody against THP were detected in seven of 34 challenged rabbits. Tubulointerstitial nephritis was found in six of the seven rabbits with elevated antibody as well as in 19 of 27 rabbits without elevated antibody. By contrast, peripheral lymphocytes from eight of 13 rabbits with tubulointerstitial nephritis were cytotoxic against target fibroblasts in the presence of THP as compared to none of eight age matched challenged or unchallenged rabbits with normal kidneys. The presence or absence of endotoxin in vitro did not influence determinations of antibody-or lymphocyte-mediated cytotoxicity. These observations suggest that the tubulointerstitial nephritis which develops in rabbits challenged with THP is primarily the result of cell-mediated immune responses directed against THP, and does not require the presence of endotoxin in the challenge solution, or serum IgG antibodies directed against THP.