A national study was conducted to determine the in vitro activity of 2 newer macrolides, dirithromycin and erythromycylamine compared with that of erythromycin, tetracycline and penicillin. Nineteen major teaching hospitals participated in the study. Minimal Inhibitory Concentrations (MICs) were determined by agar dilution, mostly using Iso-Sensitest Agar and an inoculum of 10(4) cells per spot. 2284 clinically significant strains were isolated in late 1991 and early 1992, comprising 1736 Gram-positive cocci, 355 Haemophilus influenzae, 97 Moraxella catarrhalis, 32 Listeria monocytogenes, 25 Neisseria meningitidis and 39 Neisseria gonorrhoeae were tested. The study indicates that dirithromycin and erythromycylamine possess antibacterial activity equivalent to that of erythromycin against most Gram-positive cocci and M. catarrhalis. Strains resistant to erythromycin were also resistant to dirithromycin and to erythromycylamine. Tetracycline was as active as the macrolides against both penicillin-resistant and penicillin-susceptible strains of Staphylococcus aureus. Coagulase-negative penicillin-resistant staphylococci, compared with tetracycline, were relatively resistant to the macrolides. H. influenzae was less susceptible than the Gram-positive cocci.