The in vitro activity of linezolid against common Gram-positive pathogens was compared to that of penicillin or ampicillin or oxacillin (depending upon genus), cefazolin, erythromycin, clindamycin, quinupristin/dalfopristin, levofloxacin, nitrofurantoin and vancomycin by disk diffusion methods. One hundred and six centers (31 states in US) tested recent clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecium, E. faecalis, Streptococcus pneumoniae, and other streptococci. Testing was conducted using the standardized disk diffusion method and concurrent quality control testing was performed. Strains with linezolid zone diameters of < or = 20 mm were requested for referral to the microbiology monitor for confirmation. A total of 3,100 isolates (97% compliance) were tested. Susceptibility (zone diameters, > or = 21 mm) of staphylococci and streptococci to linezolid was reported in 100% and 99.4% of staphylococci and streptococci, respectively. Susceptibility (zone diameters, > or = 23 mm) of enterococci to linezolid was 96.0% with only three isolates (0.4%) reported as resistant (zone diameters, < or = 20 mm; unconfirmed). Among a total of nine isolates (0.3%) reported to have zone diameters 20 mm, six were not submitted for further testing, two were contaminated with Gram-negative bacilli and one was determined to be linezolid-susceptible. There were no differences in linezolid susceptibility in the vancomycin- or oxacillin- or penicillin-resistant subsets of strains. This susceptibility pattern for US medical centers is indicative of the excellent and nearly complete in vitro activity against the key Gram-positive pathogens for which linezolid has received US Food and Drug Administration indications for clinical use.