The in-vitro activities of azithromycin and erythromycin were compared against 689 clinical isolates, including Gram-positive cocci, Haemophilus influenzae , and anaerobes. Of the 100 methicillin-susceptible isolates of Staphylococcus aureus tested, 77% were susceptible to 1 mg/l azithromycin and 0.5 mg/l erythromycin, whereas 22% were resistant to 32 mg/l of both compounds. All methicillin-resistant S. aureus isolates were highly resistant to both macrolides (MIC > 64 mg/l). Coagulase-negative staphylococci showed a wide range of susceptibilities to both compounds; MIC 90 values for azithromycin and erythromycin for all isolates were 0.5 and 0.25 mg/l, respectively. With the exception of enterococci, both macrolides showed similar activity against streptococci; MIC 90 , values for both group A and group B streptococci were 0.03 and 0.06 mg/l for erythromycin and azithromycin, respectively. Azithromycin was less active than erythromycin against enterococci, with mode MICs of 4.0 and 1.0 mg/l, respectively; about 20% of isolates were highly resistant to both compounds. Azithromycin was substantially more active than erythromycin against H. influenzae ; 41% of isolates were inhibited by 0.5 mg/l azithromycin and all isolates were inhibited by 2 mg/l. The MIC 90 , for erythromycin was 8 mg/l; 36% of isolates required concentrations of ≥ 4 mg/l for inhibition. The anaerobic bacteria tested showed similar susceptibility to both azithromycin and erythromycin.