Four patients with pleuropulmonary complications attributed to community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) positive for Panton-Valentine leukocidin (PVL) are described. These patients presented to Barnes-Jewish Hospital with severe necrotizing pneumonia, empyema, ARDS-complicating pneumonia, and ventilator-associated pneumonia-complicating acute pancreatitis, respectively. The first three patients had influenza-like illnesses preceding their PVL-positive CAMRSA infections. In all four cases, PVL-positive CAMRSA was isolated from respiratory secretions, and from blood cultures in three of the individuals. Antimicrobial therapy was inappropriate initially in all four patients. Three patients failed to respond to subsequent treatment with vancomycin, including two patients with persistent bacteremia despite at least 48 h of treatment with vancomycin. These patients were subsequently treated with antimicrobials inhibiting exotoxin production (linezolid or clindamycin) with good clinical results. Clinicians should be aware of PVL-positive CAMRSA due to the rapid and severe progression of pleuropulmonary complications associated with this infection. Additionally, specific antimicrobial therapy directed against CAMRSA differs from the traditional antimicrobial agents prescribed for community-acquired pneumonia. Antimicrobial agents that specifically inhibit exotoxin production appear to be the preferred treatment agents.