In 1999, all clinical Staphylococcus aureus isolates from patients admitted to a Belgian University hospital were tested for decreased vancomycin susceptibility. Three vancomycin-intermediate Staphylococcus aureus (VISA) and four hetero-VISA strains were detected among 2145 isolates tested. They emerged from strains that belonged to locally endemic methicillin-resistant S. aureus (MRSA) genotypes in three patients who had received repeated courses of vancomycin therapy. A cystic fibrosis patient with MRSA/VISA-associated broncho-pulmonary exacerbation was successfully treated by continuous vancomycin infusion plus fusidic acid followed by oral minocycline-fusidic acid. Two other patients had VISA recovered from specimens of undetermined clinical significance. Emergence of VISA variants of endemic MRSA strains in Belgium warrants active microbiological surveillance and careful monitoring of vancomycin therapy. Therapy with high-dose vancomycin administered by continuous infusion in combination with other antimicrobials may be a therapeutic option worth investigating for VISA infection.