The aim of this study was to examine pharmacokinetics and pulmonary antibiotic tissue concentrations (PATC) of gentamicin and vancomycin after intrapulmonary administration of a perfluorodecaline (PFD)-gentamicin and a PFD-vancomycin emulsion during partial liquid ventilation (PLV). PLV was initiated in 19 healthy rabbits and 18 surfactant-depleted rabbits. The animals were randomized to receive either 5 mg/kg gentamicin and 15 mg/kg vancomycin intravenously, or 5 mg/kg gentamicin intrapulmonary, or 15 mg/kg vancomycin intrapulmonary. Antibiotic plasma levels were measured after 15, 30, 45, and 60 min, and hourly thereafter. After 5 h animals were sacrificed and lungs were removed to evaluate PATC and histology. PATC were significantly higher after intrapulmonary administration of both gentamicin and vancomycin. In healthy rabbits, peak plasma concentrations were lower and 5 h plasma concentrations were higher after intrapulmonary administration, whereas plasma concentrations were not different in surfactant-depleted rabbits. There were no differences in lung histology, hemodynamics, lung mechanics, or gas exchange between the treatment groups. We conclude that during PLV, higher PATC can be achieved after intrapulmonary administration of PFD-antibiotic emulsions compared with intravenous administration of the same dose without apparent short-term adverse effects. We speculate that intrapulmonary antibiotic administration during PLV may be beneficial in treating severe pneumonia.