Background: PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) was established in 2000 to monitor antimicrobial resistance among respiratory tract pathogens across the United States. Methods: During 2000 to 2001, 75 southern US centers collected 3,867 Streptococcus pneumoniae, 1,455 Streptococcus pyogenes and 1,042 Haemophilus influenzae. Results: Overall, 46.1% of S. pneumoniae isolates were nonsusceptible to penicillin, 35.8% were resistant to erythromycin, and 0.5% were resistant to fluoroquinolones. Against S. pneumoniae the most active agents were telithromycin (99.7% susceptible), linezolid (99.8%) and the fluoroquinolones (levofloxacin 99.4%, gatifloxacin 99.5%). The prevalence of erythromycin-resistant S. pyogenes isolates was 4.5%. Telithromycin, at concentration of ≤ 1 mg/L, inhibited 99.9% of S. pyogenes. The prevalence of β-lactamase positive H. influenzae was 26.2%. Telithromycin was active (MIC90 4 mg/L) against H. influenzae, irrespective of β-lactamase production. Conclusion: The prevalence of penicillin and macrolide resistance among respiratory tract pathogens from the southern United States is high. Fluoroquinolone resistance is low. Telithromycin is highly active against respiratory tract pathogens with reduced susceptibility to β-lactams, macrolides, and fluoroquinolones.