While surfactant (SF) therapy alone improves RDS-associated gas exchange and lung stability, absence of anti-inflammatory proteins limits efficacy with respect to inflammation. CC10, deficient in preterm infants, prevents surfactant degradation and has anti-inflammatory properties. In this study, intratracheal (IT) rhCC10 (Claragen Inc.) augmented SF (Survanta, Ross) therapy was examined in a premature lamb model of RDS with respect to inflammation and kinetic dose-response profiles. Preterm lambs (n=24; gest age: 126+/-3d) were delivered via cesarean section, sedated, ventilated and randomized into groups: 100-mg/kg SF, 100-mg/kg SF followed by 0.5-mg/kg rhCC10, 100-mg/kg SF followed by 1.5-mg/kg rhCC10, 100-mg/kg SF followed by 5.0-mg/kg rhCC10. Arterial blood chemistry and lung mechanics were monitored; lungs were lavaged and snap-frozen after 4 hours. TNF, IL-8 in plasma; TNF, IL-6, IL-8, myeloperoxidase in lung; and rhCC10 in plasma, urine, BAL and lung were analyzed. Improvement in compliance, PIP and VEI was greatest (p<0.05) with SF+5.0-mg/kg rhCC10. Plasma, urine, BAL and lung [rhCC10] increased (p<0.01) with dose. Plasma [IL-8] was lower (p<0.05) with rhCC10 than surfactant alone. Treatment with at least 1.5-mg/kg rhCC10 resulted in lower (p<0.05) lung [TNF], [IL-8] and [myeloperoxidase]; SF+1.5-mg/kg rhCC10 group had lower (p<0.05) lung [IL-6], compared to all other groups. Compared to surfactant alone, surfactant augmented with at least 1.5-mg/kg rhCC10 decreased RDS-induced lung and systemic inflammation. Given that inflammation may lead to functional compromise, these data suggest that early intervention with rhCC10 may enhance surfactant therapy and warrant longer duration studies to determine its role to decrease long-term complications of ventilator management.