Surveillance for emerging linezolid resistance among commonly occurring Gram-positive pathogens in the United States began with the 2002 ZAAPS program and more recently (2004) expanded as the LEADER program. The 2006 LEADER program processed 5374 strains from 50 medical centers (100 per site) located within the 9 US census regions; species and number tested by broth microdilution (% linezolid susceptible) included Staphylococcus aureus (2913, >99.9), coagulase-negative staphylococci (CoNSs) (808, 98.4), enterococci (547, 97.4), Streptococcus pneumoniae (546, 100.0), viridans group streptococci (189, 100.0), and beta-hemolytic streptococci (371, 100.0). In addition to 1 linezolid-nonsusceptible S. aureus, 3 strains were daptomycin-nonsusceptible, 4 were quinupristin/dalfopristin-intermediate, 2 were vancomycin-intermediate (vancomycin MIC values, 4 mug/mL), and all were methicillin-resistant S. aureus. Among the linezolid-resistant isolates (1 S. aureus, 13 CoNSs, 3 Enterococcus faecalis, and 10 Enterococcus faecium isolates), all but 3 Staphylococcus epidermidis isolates had the G2567T mutation. Overall, 99.55% of the tested 2006 LEADER program isolates remained susceptible to linezolid at current Clinical and Laboratory Standards Institute breakpoints.