How to eradicate methicillin-resistant Staphylococcus aureus (MRSA) colonization in hospitalized patients is uncertain. We reviewed our experience with MRSA decolonization therapy in hospitalized patients. An 1100-bed, university-affiliated tertiary care teaching hospital in Toronto, Ontario. Retrospective chart review of 207 adult inpatients with MRSA colonization hospitalized between February 1996 and March 1999. All patients with MRSA colonization were assessed for possible decolonization therapy with a combination of 4% chlorhexidine soap for bathing and washing, 2% mupirocin ointment applied to the anterior nares three times/day, rifampin (300 mg twice daily) and either trimethoprim/sulfamethoxazole (160 mg/800 mg twice daily) or doxycycline (100 mg twice daily). This treatment was given for seven days. A total of 207 hospitalized patients with MRSA colonization were identified and 103 (50%) received decolonization therapy. Patients who received decolonization therapy were less likely than untreated patients to have intravenous (P=0.004) or urinary catheters (P<0.001), or extranasal sites of colonization (P=0.001). Successful decolonization was achieved in 90% of the 43 patients who were available for at least three months of follow-up. Combined topical and oral antimicrobial therapy was found to be effective in eradicating MRSA colonization in selected hospitalized patients, especially those without indwelling medical devices or extranasal sites of colonization.