Résumé : We assessed the in vitro susceptibility of Streptococcus pneumoniae isolates from patients with confirmed community-acquired pneumonia (CAP) to β-lactams, macrolides and fluoroquinolones and the association of non-susceptibility and resistance with serotypes/serogroups (STs/SGs), patient's risk factors and vaccination status. Samples (blood or lower respiratory tract) were obtained in 2007-2009 from 249 patients (from seven hospitals in Belgium) with a clinical and radiological diagnosis of CAP [median age 61 years (11.6% aged <5 years); 85% without previous antibiotic therapy; 86% adults with level II Niederman's severity score]. MIC determination (EUCAST breakpoints) showed for: (i) amoxicillin, 6% non-susceptible; cefuroxime (oral), 6.8% resistant; (ii) macrolides: 24.9% erythromycin-resistant [93.5% erm(B)-positive] but 98.4% telithromycin-susceptible; and (iii) levofloxacin and moxifloxacin, all susceptible. Amongst SGs: ST14, all resistant to macrolides and most intermediate to β-lactams; SG19 (>94% ST19A), 73.5% resistant to macrolides and 18-21% intermediate to β-lactams; and SG6, 33% resistant to clarithromycin. Apparent vaccine failures: 3/17 for 7-valent vaccine (children; ST6B, 23F); 16/29 for 23-valent vaccine (adults ST3, 7F, 12F, 14, 19A, 22F, 23F, 33F). Isolates from nursing home residents, hospitalised patients and patients with non-respiratory co-morbidities showed increased MICs for amoxicillin, all β-lactams, and β-lactams and macrolides, respectively. Regarding antibiotic susceptibilities: (i) amoxicillin is still useful for empirical therapy but with a high daily dose; (ii) cefuroxime axetil and macrolides (but not telithromycin) are inappropriate for empirical therapy; and (iii) moxifloxacin and levofloxacin are the next 'best empirical choice' (no resistant isolates) but levofloxacin will require 500 mg twice-daily dosing for effective coverage.