Throat swab specimens were obtained from 3,227 children with symptoms of acute pharyngotonsillitis. After 14 to 21 days, a second throat swab specimen was obtained at a follow-up visit. Over 42% of the 934 strains of Streptococcus pyogenes isolated in the primary study were resistant to erythromycin, azithromycin, and clarithromycin. Eradication rates among the 668 patients who entered the follow-up study were as follows: 84.1%, penicillin recipients; 82.7%, cephalosporin recipients; and 71.7%, macrolide recipients. Among patients treated with macrolides, the eradication rate was approximately 80% when the infecting organisms were erythromycin-susceptible and approximately 60% when they were erythromycin-resistant. These results indicate substantial in vitro macrolide resistance among Italian isolates of S. pyogenes. However, at least for a minor self-limiting condition such as acute S. pyogenes pharyngitis, our findings point to a limited overall correlation between in vitro susceptibility (to penicillins, cephalosporins, or macrolides) and eradication in patients treated with these drugs and an even weaker correlation between in vitro resistance (to macrolides) and noneradication in patients receiving macrolide therapy.