The role of the major cell wall components of Staphylococcus aureus in the leukopenia, thrombocytopenia, and complement activation associated with S. aureus bacteremia was studied in a guinea pig model. Formalin-linked S. aureus strains HSm(R), 52A5, Cowan I, and Cowan EMS and purified peptidoglycan were used. Normal animals given peptidoglycan developed early (5-min) leukopenia, thrombocytopenia, and depletion of C3-C9 hemolytic activity similar to values in animals given killed S. aureus organisms and C4-deficient animals challenged with peptidoglycan. Cobra venom factor-treated animals challenged with peptidoglycan did not develop early leukopenia and thrombocytopenia, but all animal groups persistently had late (>1-hr) leukopenia and thrombocytopenia. This observation suggests that peptidoglycan may play a major role in the early leukopenia and thrombocytopenia associated with S. aureus bacteremia in the guinea pig and that these effects can be mediated by activation of the alternative complement pathway alone. Peptidoglycan also causes a late leukopenia and thrombocytopenia which may occur independently of complement activation.