The efficacy of an antibiotic in the treatment of bacterial infections depends upon the interactions of drug, bacteria, and phagocytes. In an examination of certain of these interactions, overnight cultures of 3H-labeled Staphylococcus aureus were briefly incubated in the presence or absence of various antibiotics prior to phagocytosis by rabbit alveolar macrophages. Preincubation of organisms with an inhibitor of bacterial protein synthesis (clindamycin, erythromycin, chloramphenicol, or rifampin) but not with a cell wall-active drug (penicillin G or cefazolin) led to an increase in phagocytosis and early intracellular killing by alveolar macrophages. Antibiotic-mediated susceptibility of S aureus to ingestion by alveolar macrophages correlated with the inhibition of bacterial protein synthesis. Clindamycin-treated staphylococci were more efficiently opsonized by heat-inactivated serum and bound larger amounts of specific antibody than did control organisms. Thus, compromise of one or more antiphagocytic surface components secondary to decreased protein synthesis is the means by which certain antibiotics influence bacterial susceptibility to the antimicrobial mechanisms of phagocytes. This effect may be an important determinant in the success of treatment with inhibitors of bacterial protein synthesis.