This study shows a significant association between the number of macrolide prescriptions reimbursed by the Italian National Health Service and resistance of Streptococcus pyogenes to erythromycin in children from a region in northern Italy with high prevalence of erythromycin resistance. Recent prescription of a macrolide (especially azithromycin) is a predictor of erythromycin resistance, as well as a possible risk factor for resistance at a community level.