Sitafloxacin is a new quinolone active against multi-resistant Gram-positive pathogens. An open study was conducted in patients with serious systemic infections with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE). Patients with MRSA were recruited if treatment with glycopeptides had failed. Of 11 patients with MRSA infection, four were cured, six failed treatment and one was indeterminate. Of nine patients with VRE infection (one patient had both pathogens), five were cured and four failed. Fifteen adverse events in 12 patients were potentially related to the study drug. Sitafloxacin was effective in VRE and some recalcitrant MRSA infections.