Background: The Tigecycline Evaluation and Surveillance Trial (TEST) was initiated in 2004 to chart the activity of tigecycline and comparator antimicrobial agents against gram-positive and gram-negative organisms globally. Objectives: This study aimed to provide an analysis of the antimicrobial susceptibility of gram-positive organisms collected from the 9 census regions of the United States between 2004 and 2009. Methods: The MICs and antimicrobial susceptibility were determined using Clinical and Laboratory Standards Institute methodology. For tigecycline, US Food and Drug Administration susceptibility criteria were used. Results: A total of 8782 Staphylococcus aureus isolates (54.5% methicillin-resistant S aureus) were collected, with the highest percentage of MRSA isolates collected from the South Central region (67.9%). All S aureus isolates were susceptible to tigecycline, linezolid, and vancomycin. Overall, 4.6% of Enterococcus faecalis (n = 3753) and 69.1% of Enterococcus faecium (n = 1417) isolates were vancomycin resistant, with the highest rates in the East North Central region for E faecalis (7.1%) and the South Atlantic region for E faecium (79.5%). Small numbers of linezolid nonsusceptible E faecalis (n = 13) were identified. MIC90 values for tigecycline were <= 0.2.5 mg/L against E faecalis and 0.12 mg/L against E faecium. Of the Streptococcus pneumoniae isolates collected (n = 4541), 1.1% were penicillin resistant. All S pneumoniae isolates were susceptible to linezolid and vancomycin; susceptibility to tigecycline varied between 80.9% (Pacific region) and 95.2% (West North Central region). Conclusions: The rates of MRSA and vancomycin-resistant Enterococcus spp varied among the 9 census regions; however, susceptibility to linezolid, vancomycin, and tigecycline remained consistent, with low MIC90 values and high rates of antimicrobial susceptibility. (Clin Ther. 2011;33:1964-1973) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.