The use of levofloxacin in critically ill patients has progressively increased since commercial marketing of the drug in 1999, despite the fact that few studies have been designed to assess the use of levofloxacin in this population. Pharmacological characteristics, broad spectrum of activity, and tolerability account for the high interest in the drug for the treatment of different infectious diseases, including ventilator-associated pneumonia (VAP), and the recommendation of levofloxacin in guidelines developed by a number of scientific societies. According to pharmacokinetic–pharmacodynamic data, it seems reasonable to assume that an increase in activity follows from a larger dose, so that 500 mg/12 h is adequate in patients with VAP. In critically ill patients with VAP, levofloxacin monotherapy is indicated for empirical treatment of patients with early onset pneumonia without risk factors for multiresistant pathogens, and in combination therapy for late onset VAP or for patients at risk for multiresistant pathogens. The use of levofloxacin in combination therapy is supported by multiple reasons, including: increased empirical coverage in infections with suspected intracellular pathogens; substitution for more toxic antimicrobial agents (e.g., aminoglycosides) in patients with renal dysfunction and in those at risk for renal insufficiency; and severity of systemic response to infection (septic shock) that justifies multiple treatment with better tolerated antibiotics. The availability of the oral formulation allows sequential therapy, switching from the intravenous route to the oral route. Levofloxacin is well tolerated by critically ill patients, with few adverse events of mild to moderate severity.