Streptococcus pneumoniae strains have exhibited decreasing susceptibility to penicillins and macrolides during the past several years. We reviewed the medical charts of all patients with pneumococcal bacteremia who were admitted to a university hospital over a period of 1 year, to identify failures of outpatient therapy. Of 41 patients admitted with pneumococcal bacteremia, 4 had previously taken either azithromycin or clarithromycin for 3-5 days. All 4 had pneumococcal strains that exhibited low-level resistance to macrolide antibiotics. Among pneumococci, low-level resistance to macrolides can lead to clinical failure, and resistance to macrolides should be considered during the selection of empiric therapy for patients with presumed pneumococcal infections.