Purified peptidoglycan (PG) obtained from Neisseria gonorrhoeae was tested for the ability to consume complement in normal human sera. Sonicated PG (S-PG), a heterogeneous mixture of soluble fragments (molecular weight, greater than 10(6)), as well as intact (insoluble) PG, reduced the level of whole hemolytic complement in a pool of four human sera. The minimal concentration of S-PG required for this activity was approximately 500 micrograms of S-PG per ml of serum. Complete lysozyme digestion of S-PG, yielding PG fragments of less than 10(4) molecular weight, eliminated complement-consuming activity. S-PG-mediated complement consumption resulted in depletion of the individual complement components C4 and C3. Consumption of complement did not occur when C4-deficient human serum or normal human sera treated with Mg2+-(ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid to specifically impair classical complement pathway activity were used. The addition of rabbit anti-PG antibody greatly enhanced gonococcal PG-mediated complement consumption. Together, the data suggested that gonococcal PG-mediated complement consumption occurred via the classical complement pathway, was dependent on the presence of anti-PG antibody, and required glycosidically linked polymers of PG. Individual human sera varied widely in the extent of gonococcal PG-mediated reduction of complement levels, presumably a reflection of either different amounts of natural antibody to gonococcal PG, different levels of human PG hydrolase(s) capable of degrading PG to inactive fragments, or both.