Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). ARDS treatment is frequently complicated by significant extrapulmonary co-morbidity. This study was designed to clarify the role of iNOS in mediating extrapulmonary co-morbidity in sheep after combined burn and smoke inhalation injuries using a potent and highly selective iNOS dimerization inhibitor, BBS-2. Twenty-two female sheep were operatively prepared. After 5 days recovery, tracheostomy was performed under ketamine / halothane anesthesia. Sheep were given a 40% total body surface 3^rd degree burn and insufflated with cotton smoke (48 breaths, <40°C). Sheep were divided into 4 groups: sham (non-injured, non-treated, n=6), sham/BBS-2 (non-injured but, treated with BBS-2, n=4), control (injured but, non-treated, n=6) and BBS-2 (injured, but treated with BBS-2, 100 ug/kg/hr, n=6). Evaluation was in a laboratory ICU setting for 48 hrs. The sham group had stable cardiopulmonary and systemic hemodynamics. Control animals showed multiple signs of morbidity. Decreased left ventricle stroke work index (LVSWI) and stroke volume index (SVI) with elevated left atrial pressure indicated myocardial depression. Systemic vascular leak was evidenced by robust hemoconcentration, decreased plasma oncotic pressure and increased transvascular fluid flux into the lymphatic system. Finally, severely impaired renal function (urinary output) was associated with adverse net fluid balance. Treatment with BBS-2 prevented all these morbidities without adversely effecting cardiovascular hemodynamics such as cardiac index and mean arterial pressure. The results identify a major role for iNOS in mediating extrapulmonary co-morbidity in a clinically relevant and severe trauma model and support the use of highly selective iNOS inhibitors as novel treatments in critical care medicine.