In the study we characterized the macrolide sensitivity of recent clinical isolates of Streptococcus pyogenes and S. pneumoniae collected from major Saudi Arabian hospitals. Susceptibility testing was performed using standard National Committee for Clinical Laboratory Standards methodology on 335 S. pyogenes and 350 S. pneumoniae isolates. Macrolide resistance mechanism phenotypes were identified using double-disk diffusion. All S. pyogenes were penicillin sensitive, while 6.3% were macrolide resistant, the main mechanism of which was of M phenotype (96%). Approximately 51% of S. pneumoniae were penicillin non-susceptible. Macrolide resistance in S. pneumoniae accounted for 18.8%, the majority of which were M phenotype (91%). Low-level resistance mediated by mef-bearing strains pre-dominated. Newer macrolides, including azithromycin, are still considered drugs of choice for empirical treatment of respiratory infection in such circumstances.