Autoimmune tubulointerstitial nephritis (TN) was induced in strain XIII and Hartley but not strain II guinea pigs after immunization with rabbit tubular basement membranes (TBM) in CFA. Strain XIII guinea pigs developed extensive autoimmune TN associated with high anti-TBM (aTBM) antibody titers and linear deposits of IgG along renal cortical TBM after immunization with 10 mug to 10 mg of TBM. In addition, autoimmune TN was passively transferred to strain XIII animals by the i.p. injection of aTBM sera obtained from actively immunized Hartley guinea pigs. In contrast, strain II guinea pigs did not develop autoimmune TN after active immunization (10 mug to 10 mg) with rabbit TBM in CFA, and only produced high aTBM antibody titers with the highest immunnizing antigen dose. At this dose (10 mg) the strain II animals demonstrated linear deposits of IgG along renal cortical TBM but did not develop autoimmune TN. Further, recipient strain II guines pigs did not develop autoimmune TN after passive transfer of aTBM antisera despite renal cortical tubular deposition of aTBM antibodies. Both inbred guinea pig strains produced antibodies reactive with rabbit and rat renal basement membranes. No evidence for differences in nephritogenic TBM antigens could be demonstrated betweed strain XIII and strain II TBM. These observations indicate that 1) genetic factor(s) influence the production of antibodies reactive to autologous TBM, 2) after the deposition of antibodies on the TBM, additional or related genetic factor(s) determine the full expression of this autoimmune renal disease, and 3) aTBM antibody deposition on renal TBM is not sufficient to elicit autoimmune TN.