We modified our established and clinically relevant ARDS model of smoke inhalation injury and septic shock by administration of combined antibiotics (AB) such as piperacillin and ciprofloxacin, to more closely mimic the clinical intensive care setting. Twenty-three sheep were subjected to the injury, and allocated to four groups for a 96h study period: sham (n=5 non-injured); control (n=6: injured); AB6h (n=6: injured, antibiotics started 6h post-injury); AB12h (n=6: injured, antibiotics started 12h post-injury). All sham animals survived 96h. Control, AB6h, AB12h groups reached criteria of septic shock within 12h post-injury. All controls died within 36h. Eighty three percent of AB6h and fifty percent of AB12h survived 96h. Median survival times were significantly improved in the treated groups compared with the control group: 24h in control vs. 80.5h in AB6h, and 65h in AB12h animals. Combined ciprofloxacin and piperacillin therapy was effective, reduced nitric oxide production and mortality, and will allow future long-term studies in this model.