The macrolide-resistance rate among group A Streptococcus (GAS) isolates has increased in some European countries. To investigate the reasons for this increase, the ability of 60 erythromycin-resistant and 61 erythromycin-susceptible, genetically unrelated, pharyngeal GAS isolates from Spain to enter and persist within human keratinocytes was evaluated. It was observed that erythromycin resistance was associated with the presence of prtF1, a gene related to invasiveness, whereas no association was observed with the ability to enter human keratinocytes. However, the ability to enter human keratinocytes was not associated with the presence of prtF1 or with the emm type, suggesting that interaction with keratinocytes depends on several characteristics of the isolate. Almost all strains (95.9 %) were capable of persisting within human keratinocytes. However, most of them (91.7 %) exhibited a decline in viability over time. Interestingly, the ability to persist within keratinocytes protected from the action of the beta-lactams was higher among erythromycin-resistant isolates and correlated with their ability to avoid the induction of cellular lysis. These observations suggest that if the carrier state results from intracellular GAS survival, the association between erythromycin resistance and intracellular persistence may represent a serious problem for the eradication of these isolates.