Macrolide resistance is a major concern in the treatment of Streptococcus pneumoniae. Inducible macrolide resistance in this pneumococcus is mediated by the efflux pump MefE/Mel. We show here that the human antimicrobial peptide LL-37 induces the mefE promoter and confers resistance to erythromycin and LL-37. Such induction may impact the efficacy of host defenses and of macrolide-based treatment of pneumococcal disease.