Vancomycin therapy is the standard treatment for methicillin-resistant Staphylococcus aureus (MRSA), the most common cause of vertebral osteomyelitis, an increasingly frequent complication of nosocomial bacteremia. We report five recent cases suggesting that, while giving the appearance of success by conventional clinical and laboratory criteria (eg, resolution of fever and leukocytosis), vancomycin monotherapy may in fact be insufficient to prevent or reverse the progression of hematogenous MSRA vertebral osteomyelitis. A review of the literature and possible therapeutic alternatives are also discussed.