Erythromycin resistance rates among penicillin-susceptible Streptococcus pneumoniae were 38 and 92% among penicillin-intermediate and -resistant S. pneumoniae isolates from Hong Kong, respectively, and 27% (43 of 158) of the isolates showed the MLS(B) phenotype, and the majority carried the ermB gene; 73% (115 of 158) displayed the M phenotype, and all possessed the mef gene. The MLS(B) phenotype was predominant in penicillin-susceptible, macrolide-resistant isolates and in penicillin-nonsusceptible isolates of serotype 6B, whilst the M phenotype was predominant in penicillin-intermediate or -resistant isolates belonging to serotype 23F or 19F. Extensive spread of clones of drug-resistant pneumococci has led to the widespread presence of macrolide resistance in S. pneumoniae in Hong Kong.