Clostridium difficile infection (CDI) remains a major healthcare problem associated with antibiotic use in hospitals. Recent years have seen a dramatic increase in the incidence of CDI in the UK and internationally. Lower respiratory tract infections (LRTIs) are the leading indication for antibiotic prescription in hospitals and are therefore a critical battleground in the fight against inappropriate antibiotic use and healthcare-associated infections. This article reviews the evidence for interventions to reduce CDI in hospitalized patients with LRTIs. Reducing prescriptions of cephalosporins and fluoroquinolones in favour of penicillin-based regimens and increased use of tetracyclines have been proposed. Expanding outpatient management of LRTIs and reducing length of hospital stay will limit patient exposure to the healthcare environment in which C. difficile is most easily acquired. Intravenous (iv) broad-spectrum antibiotics are often prescribed when narrower spectrum, oral antimicrobials would be equally effective and, in a proportion of patients, antibiotic therapy is used unnecessarily. Shorter antibiotic regimes may be as effective as prolonged therapy and reduce antibiotic-related complications. Early switch from iv to oral therapy allows simpler antibiotic regimens and facilitates early discharge from hospital. Simple improvements in the management of LRTIs have the potential to reduce the incidence of healthcare-associated infections.