It is important to identify the optimal dosage and best method of infusion of parenteral vancomycin to be used over a several week period for the treatment of osteomyelitis. A retrospective study was undertaken to compare a high dose vancomycin treatment (HD: 40 mg/kg/d) with a standard dose treatment (SD: 20 mg/kg/d), and also to compare the modality of infusion using either intermittent vancomycin infusion (IVI) or continuous vancomycin infusion (CVI). 89 patients with Gram-positive cocci osteomyelitis requiring vancomycin treatment were followed, and the outcome and therapeutic safety were compared. There were significantly more adverse drug reactions (acute renal failure) in the IVI subgroup (HD-IVI vs SD-IVI, p-value 0.007). No cases of renal failure were found in the HD-CVI subgroup. The best outcome was found in the subgroup of patients who received HD-CVI (HD-CVI vs SD-IVI, overall log rank p-value 0.02). HD-CVI treatment appears to provide an improved outcome with fewer adverse drug reactions.