Two ketolides, telithromycin and HMR 3004, were evaluated for their in vitro activity against erythromycin-susceptible and -resistant strains of Streptococcus pyogenes and Streptococcus pneumoniae. On the basis of their resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, erythromycin-resistant test strains were assigned to the constitutive resistance (cMLS) phenotype, the inducible resistance (iMLS) phenotype or the Rn phenotype. iMLS S. pyogenes strains were further subdivided into the three recently described subtypes iMLS-A, -B and -C. Telithromycin and HMR 3004 were uniformly and highly active against pneumococci (regardless of their susceptibility or resistance to erythromycin and/or penicillin), erythromycin-susceptible S, pyogenes and erythromycin-resistant S. pyogenes strains of the M phenotype (in which resistance is mediated by an efflux system) or iMLS-B or -C phenotype (in which resistance is mediated by a methylase encoded by the ermTR gene). Both ketolides were less active against erythromycin-resistant S. pyogenes strains with the cMLS phenotype or the iMLS-A subtype (where resistance is mediated by a methylase encoded by the ermAM gene), these strains ranging in phenotype from the upper limits of susceptibility to low-level resistant.