The incidence of penicillin- and erythromycin-resistant strains of Streptococcus pneumoniae has increased considerably in Belgium. The medical charts of all patients with pneumococcal bacteraemia who were admitted to hospital over a period of 3 years (n = 136) were reviewed to identify treatment failure of outpatient antibiotic therapy. Twelve patients had received antibiotics for at least 48 h prior to admission. Four treatment failures received clarithromycin as pre-hospitalization therapy, and S. pneumoniae from all four patients were highly resistant to macrolides. Five patients failed on co-amoxiclav, whereas their S. pneumoniae were susceptible to penicillin and amoxicillin. This observation suggests that macrolide resistance is clinically relevant and leads to treatment failure, whereas suboptimal dosing may explain breakthrough pneumococcal bacteraemia in beta-lactam-treated patients.