To investigate the role of macrophages in the induction of the production of antibody to staphylococcal antigens, we used Cl2MDP (clodronate) liposomes as a tool for local macrophage depletion. Macrophage depletion caused in mice by intraperitoneal (i.p.) injection of Cl2MDP liposomes was associated with a reduction in the clearance of Staphylococcus aureus Cowan 1 bacteria from the tissues of infected animals and with a marked decrease in the bactericidal activity of macrophages escaping from the lethal effect of clodronate. Despite the functional defect of macrophages, the mice treated with Cl2MDP liposomes two days before the injection of alpha-toxin (toxoid) or whole heat-killed S. aureus Cowan 1 bacteria, demonstrated an enhancement in the production of anti-staphylococcal alpha-toxin IgM and anti-collagen-binding protein IgG. A similar enhancement of antistaphylococcal antibody synthesis was observed in mice after receiving phosphate buffered saline (PBS) encapsulated in liposomes.