Lipoteichoic acids (LTA) released by gram positive bacteria can spontaneously bind to mammalian cell surfaces. Cells bearing LTA can activate either the classical or alternative pathways of complement (C') in heterologous sera. These observations suggest that the tissue damage which occurs during the course of a bacterial infection might in part be mediated by the host's C' system directed against its own cells bearing surface LTA. A model system was established using erythrocytes (E) presensitized with pneumococcal LTA (LTA-E). When LTA-E from normal rats, normal humans, normal guinea pigs, a C2-deficient human and C4-deficient guinea pigs were each incubated in their autologous sera, there was significant C'-mediated lysis in vitro. The survival of 51Cr-labelled autologous LTA-E in normal rats or cobra venom factor-treated rats (CoVF-rats) (<3% normal C3 levels) was also studied. Only 2.9% of autologous LTA-E remained in the circulation of normal rats at 90 min. In contrast, 31.2% of autologous LTA-E remained in the circulation of CoVF-rats. Intravascular hemolysis accounted for the clearance of LTA-E in the normal rats, while liver sequestration was responsible for clearance in the CoVF-rats. The survival of untreated autologous E in normal or CoVF-rats was normal (93.6% and 96.4% respectively). The results demonstrate that LTA can render cells susceptible to damage by the host's own C' system, establishing this as a possible mechanism of tissue damage in natural infections.