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We report the results of a prospective, multicenter trial assessing intravenous and oral clinafloxacin treatment for infective endocarditis. Sixty-six patients constituted the final study population. Among the 53 patients with native valve infection, Staphylococcus aureus and Streptococcus viridans were the most common pathogens. Twelve patients with native valve infection required surgery, at which time all valve tissue culture results were negative. The overall success rate for native valve infection was 87%. Single valves were involved in 11 of 13 patients with prosthetic valve endocarditis (PVE), and multiple valves were involved in 2 cases. Enterococcus faecalis was the most common pathogen, causing 4 of the PVE cases. The overall success rate for treatment of PVE was 69%. Patients with PVE who did not respond to treatment presented with complications that predict poor prognosis. Clinafloxacin may be effective for both native and PVE, but further studies are indicated.