The immunoglobulin M antibody response to the lipoteichoic acid (LTA) of Staphylococcus aureus ATCC 6538P was examined by a procedure in which erythrocytes sensitized with periodate-activated LTA were used for the detection of immunoglobulin M-producing plaque-forming cells LTA-specific plaque-forming cells were first detected 2 days after immunization with heat-killed bacterial cells, and maximal numbers of plaque-forming cells, mostly of the immunoglobulin M class rather than the immunoblogulin G or immunoglobulin A class, were attained by day 4; specificity for LTA was affirmed by plaque inhibition tests. No plaque-forming cells were found in mice given isolated LTA over a 10,000-fold range of immunizing doses. Mice pretreated with a carrier known to activate thymus-derived helper lymphocytes produced a plaque-forming cell response to LTA only when immunized with LTA bound to the same carrier. This suggests that carrier-specific thymus-derived cells are needed to initiate an antibody response to poorly immunogenic LTA. Since an antibody response can be elicited in mice given heat-killed cells, other cell wall and/or cell membrane constituents may play an important role as immunologically active carriers for this antigen.