Flavobacterium meningosepticum is an unusual, highly resistant, gram-negative bacillus that is associated with neonatal meningitis and nursery outbreaks of meningitis. The optimal therapy for this infection is not known. We successfully treated three neonates with intravenous vancomycin and rifampin. We determined the in vitro activity of meropenem, ciprofloxacin, vancomycin, linezolid (PNU-100766), and rifampin, alone and in combination, against four isolates of F. meningosepticum from neonates with sepsis and meningitis. MICs were determined by tube dilution, and fractional inhibitory concentrations were calculated with use of the checkerboard microtiter dilution technique. Synergy was observed between rifampin and vancomycin against three isolates, while combinations of vancomycin, ciprofloxacin, and linezolid showed an additive effect against all isolates. These results support the clinical evidence that the combination of vancomycin and rifampin is an appropriate regimen for neonatal meningitis due to F. meningosepticum. The combination of meropenem and vancomycin was antagonistic. The clinical efficacy of combinations including ciprofloxacin, newer quinolones, or linezolid for treating F. meningosepticum meningitis deserves further study.