The aim of this study was to determine the evolution of resistance to macrolides and other antibiotics in strains of Streptococcus pyogenes isolated in the province of Gipuzkoa, Spain. During the period 1984-1996, all 2561 strains of Streptococcus pyogenes studied showed full susceptibility to penicillin. Until 1990, only 1.2% of Streptococcus pyogenes isolates were resistant to erythromycin. Since then, resistance to erythromycin increased every year until 1995, when 34.8% (87/250) of Streptococcus pyogenes strains were found to be resistant. In 1996 the rate of resistance to erythromycin was 17.8% (75/422). During the study period, 96.1% (246/256) of the Streptococcus pyogenes isolates resistant to erythromycin were susceptible to clindamycin. Of the remaining erythromycin-resistant Streptococcus pyogenes strains, resistance to clindamycin was constitutive in seven strains and inducible in three. When investigated by the polymerase chain reaction (PCR), all Streptococcus pyogenes strains resistant to erythromycin and susceptible to clindamycin showed the 1.4 kb fragment of the mefA gene, recently described as the novel macrolide-efflux-resistance determinant. The most frequent T-agglutination patterns among Streptococcus pyogenes resistant to erythromycin were T4 and T8,25. The emergence and rapid spread of erythromycin-resistant Streptococcus pyogenes in Gipuzkoa and its relationship to the presence of the mefA gene are described.