We reviewed all patients with Staphylococcus aureus lower respiratory tract infections treated with vancomycin at our institution in 1998, to see how this antimicrobial is performing. We found that approximately 40% of evaluable patients were considered treatment failures, even though the S. aureus was still reported as being susceptible to vancomycin. We report in detail two example patients that failed to respond clinically to vancomycin and summarize the clinical characteristics of the 23 additional patients that failed. The first case was treated four times in the intensive care unit with vancomycin. Each course, after approximately 14 days therapy, the vancomycin was discontinued and his infection relapsed soon thereafter. The second was treated with vancomycin for 10 days initially. She relapsed, was restarted on vancomycin once more, but her condition deteriorated, and she died of refractory sepsis 20 days after admission. The cost of care for each patient ranged from $50,000 to over $100,000. With trends such as these, alternative therapies are needed to control resistant Gram-positive infections.