Continuing problems of antimicrobial resistance have prompted the initiation of several surveillance programs. Few, if any, of these programs focus on community-acquired respiratory tract infections seen in routine office-based practices. The Respiratory Surveillance Program (RESP; 1999–2000) in 674 community-based physician office practices in the United States determined the frequency of potential bacterial pathogens including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in patients diagnosed clinically with community-acquired pneumonia, acute exacerbations of chronic bronchitis, and sinusitis throughout all 9 US census/geographic regions. Susceptibility to the penicillins (ampicillin, penicillin), oral cephalosporins, fluoroquinolones (gatifloxacin, levofloxacin, ciprofloxacin), macrolides (erythromycin, azithromycin, clarithromycin), tetracycline, and trimethoprim/sulfamethoxazole was determined by reference methods. Patients were required to have a culturable focus of infection, and specimens were immediately sent to a reference laboratory. Among 22,689 total specimens (610 community-acquired pneumonia, 4,779 acute exacerbation of chronic bronchitis, 16,213 sinusitis, 1,087 other), H influenzae was the most commonly isolated organism from patients with community-acquired pneumonia (38%) and acute exacerbation of chronic bronchitis (35%) in all nine geographic regions. S pneumoniae was isolated in 18% of community-acquired pneumonia cases, 13% of acute exacerbation of chronic bronchitis cases, and 11% of sinusitis cases. M catarrhalis was most commonly isolated from the nasopharynx of patients with sinusitis (29%). High-level resistance to penicillin (2 μg/mL or greater; 16% overall) and the macrolides (32% to 35%) among S pneumoniae varied both with site of infection and with geographic region. The greatest resistance was observed among isolates from the nasopharynx of patients with sinusitis and from patients from the East South Central or South Atlantic regions of the United States. Although the susceptibility of H influenzae and M catarrhalis to the tested antimicrobials did not vary with the type of infection, β-lactamase-mediated resistance to ampicillin among H influenzae ranged from 15% in New England to 32% in the East South Central region. The fluoroquinolones were highly active against these cultured isolates from community-acquired respiratory tract infection patients, with >99% of all S pneumoniae, H influenzae, and M catarrhalis strains susceptible to gatifloxacin (MIC₉₀, 0.5 μg/mL) and levofloxacin (MIC₉₀, 2 μg/mL). The extended-spectrum fluoroquinolones appear well suited for community-acquired respiratory tract infection therapy, including pathogens other than pneumococcus, H influenzae, and M catarrhalis.