In Belgium more than 17% of the invasive pneumococci are not susceptible to penicillin, and more than 38% not to macrolides. The most prevalent mechanism of macrolide resistance in Europe is modification of the drug target site leading to cross-resistance to lincosamides and group B streptogramines (MLSB resistance). Telithromycin is the first antibiotic of the family of ketolides, which differ from erythromycin by having a 3-keto group instead of the neutral sugar L-cladinose. We tested the susceptibility of 637 pneumococci, recently isolated from patients in Belgium, to telithromycin and five other antibiotics. Data generated by this study show that telithromycin inhibits 98.4% of pneumococci at a breakpoint concentration of 1 mg/L in spite of a high percentage (> 30%) of strains with the MLSB constitutive type of resistance. Susceptibilities to the five comparator drugs were: penicillin (81.8%), tetracycline (67.0%), levofloxacin (98.9%), erythromycin (61.5%) and clindamycin (66.6%). Consequently telithromycin looks to have considerable potential for the empiric treatment of community-acquired respiratory tract infections.