Three classes of macrolide resistance phenotypes and three different erythromycin resistance determinants were found among 127 erythromycin-resistant group A streptococcal (GAS) isolates recovered from 355 (35.8%) pediatric pharyngitis patients in Rome, Italy. According to emm and sof sequence typing results, erythromycin-resistant isolates comprised 11 different clonal types. Remarkably, 126 of the 127 macrolide-resistant isolates were serum opacity factor (sof) gene positive. These data suggest a strong association between macrolide resistance and the presence of sof among GAS isolates recovered from Italian pediatric pharyngitis patients.