Optimal therapy of infections due to organisms capable of surviving within phagocytes would include use of antimicrobials that penetrate phagocytic cells and inactivate intracellular organisms. To establish those characteristics of drug and cell that mediate the antibiotic-phagocyte interaction, we have studied the uptake of radiolabelled antibiotics by rabbit alveolar macrophages (AM), human AM from smokers and non-smokers, and human polymorphonuclear leukocytes (PMN). Relative entries of drug groups into the three types of phagocytic cells were similar. Penicillin G and cephalosporin antibiotics were taken up poorly by phagocytes. Lipid-soluble antibiotics, such as rifampicin and chloramphenicol, were concentrated several-fold (2-5) by phagocytes. Ethambutol, erythromycin and clindamycin were concentrated many-fold (5-50) by phagocytic cells. Human AM of smokers accumulated certain antibiotics more avidly than AM of non-smokers. Clindamycin entry into phagocytes was shown to be an active, energy-requiring process, mediated by the nucleoside transport system. Ingestion of microbial particles by PMN stimulated transport of both clindamycin and nucleoside (adenosine) into the cell.